Title of Invention

"4-ANILINOQUINOLINE-3-CARBOXAMIDE OF THE FORMULA I (A)"

Abstract anilinoquinoline-3-carboxamides of formula (IA) in which Ar is phenyl substituted by ethyl, propyl, hydroxymethyl or CO2H or disubstituted by methyl and hydroxymethyl; R1 is methoxy, ethoxy or a group OCH2CONH2, OCH2CH2OCH3, or 0(CH2)PNR4R5 where p is 2 or 3 and R4 and R5 are hydrogen, methyl, ethyl or propyl or together R4 and R5 form a pyrrolidine, imidzole or morpholine ring; R2 is methoxy, ethoxy or 0(CH2)PNR4R5 where p is 2, 3 or 4 and R4 and R5 are hydrogen methyl or ethyl or one of R4 or R5 is methyl and the other is pyridyl or pyrazole or R4 and R5 form a piperidine, hydroxypiperidine, thiomorpholine, morpholine, pyrrolidine, 2,6-dimethylmorpholine imidazole or triazole ring,
Full Text The present invention relates to 4- anilinoquinoline -3-carboxamides.
Janus Kinase 3 (JAK3) is a member of the Jahus family of protem kinases. Although the other members of flus family are expressed by essentially all tissues, JAK3 expression is limited to hematopoetic cells This is consistent with its essential role m signalmg through the receptors for IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15 by non-covalent association of JAK3 with the gamma cham common to these multicham receptors. These cytoldnes all have a shared function in that they are mvolved m. lymphocyte difTerentiatian and proliferatioiL XSCID patient populations have been ideatif ed with severely reduced levels of JAIG protein or with genetic defects to the common ganuna chain, suggesting that imznunosupression should result from blocking signalmg through the JAK3 pathway Animal studies have suggested that JAK3 not only play a critical role in B- and T-lymphocyte maturation, but that JAIC3 is consbtutively required to maintain T-cell fiinction. Modulation of immune activity through this novel mechanism can prove useful m the treatment of T-cell prolifsrative disorders such as transplant rejection and autounmune diseases
The role of JAK3 m mast cells has been described in knockout mice. Thus, IgE/antigen induced degranulation and mediator release were substantially reduced in mast cells generated from JAK3 deficient mice. JAK3 deficiency does not affect mast cell proliferation m vitro, it has also been shown that IgE receptor levels and mediator contents are identical m JAK3-/- and JAK3 +/+ mast cells. Therefore, JAK3 appears essential for the complete response of IgE challenged mast cells. The role of JAK3 in mast cell activation has been well established m munne system, however, there is no published data on mast cell function m the AR-SCID patients. Targetmg JAK3 provides the basis for new and effective treatment of mast cell mediated allergic reactions
To date a number of JAK3 inhibitors has been disclosed, among them are quinazolines (Sudbeck, E. A. et al. cliniical Cancer Res. 5(1999)1569-82, WO 00/0202) and pyrrolo[2,3-d]pyiimidmes (Blumenkopf, T A. et al WO 99/65909)
In the current application compounds, 4-anilmogumohne-3-carboxamides, are claimed as JAK3 inhibitors Structurally related compounds have previously been desonbed as kmase
inhibitors e g WO 00/18761 and WO 98/43960 disclose substituted quinoline-3-carbonitrile derivatives In a recent publication (Boschelli, D H el a] J Med Chem. 44(2001)822-33) one compound of the present mvention has proved not to have any inhibitory capacity towards the activity of the protein tyrosine kinase Src JAK3 is not mentioned m any of the above literature examples.
Two compounds and their synthesis lelatmg to this invention have previously been descnbed(Boschelli, D H et al J Med Chem 44(2001)822-33 and Wissner et al WO 98/43960) (Formula Removed)
The present mvention therefore provides a compound of formula (I) for use m the manufdoture of a medicament for the Ueatment of a disease imediated by JAK3
wherein in or 1, X IS NR m O, (Formula Removed)
Ar is selected from phenyl, tetrahydron R groups are independently hydrogen or C1-C8 alkyl,
R1 and R2 are independently selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy. hydroxy, aryl, Y(CR112)PNRR, Y(CR112)pCONR4R5, Y(CR112)pCO2R6, Y(C R11)pOR6, Y(C R112)pR6.
or R1 and R2 are linked together as -OCIIzO- or-OCH2CH2O-,
R' ' groupi are independently hydrogen, C1-C8 alkyl, hydroxy or halogen,
p lb 0,1, 2, 3, 4 or 5,
Y is o\ygen, CH2 or NR'
R3 IS hydrogen or C1-C8alkyl,
R4 and R5 each independently represent hyrogen, C1-C8 alkyl or R4 and R5 together with the nitrogen atom to which they are attached foim a 4- to 7 membered saturated or aromatic heterocychc rmg system optionally conlainmg a furtheiroxygen, sulphur or NR6 group, or one of R4 and R5 is hydrogen or C1-C8alkyl and the other is a 5- or 6-membered heteiobyclic nng system optionally containing a further oxygen, sulphur or nitiogen atom,
R6 is hydiogen. C1-C8 alkyl. phenyl or benzyl,
R7 IS hydrogen or C1-C8 alkyl,
R8 IS hydrogen or C1-C8alkyl,
R9and R10 are each independently hydrogen or C1-C8 alkyl
and pharmaoeutically acceptable salts thereof
The term alkyl, whether used alone or as part of another group such as alkoxy, means any straight or branched chamed alkyl group The term aryl includes phenyl and naphthyl groups
Suitably the R groups are mdependently hydiogen or C1-C8 alkyl, preferably hydrogen or methyl, and most preferably both R groups aie hydrogen
Suitably X is NR3 or 0 Preferably X is NR3 where R3 is C1-4alkyl, more pieferably X is NH
Suitably n 0 or 1,preferably n is 0
Suitably p is 0,1,2,3,4 or 5, preferably p is 1 to 4, more pieferably p is 2 ur 3
Suitably Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrazolyl, dihydromdenyl, l-oxo-2,3-dihydiomdenyl or indazolyl optionally substituted as descnbed above Substituents can be present on any suitable position of the Ar group More than one substituenl can be present, and these can be the same oi different Preferably Ar is mdolyl or phenyl, mobt preferably phenyl
More preferably the Ar group is unsubstituted or has one or more substituents mcludmg those of compounds exemplified herein such as methyl, ethyl, propyl, butyl, thiomethyl, hydroxymethyi, bromo, fluoro, hydroxy, CO2H, CONH2, CF3 methoxymethyl, butoxymethyl, cyanometbyl, ethylammomethyJ, ammomethyl, ethylamino-2-oxoethyI, hydroxyethyl, 2-ammo-2-oxoethyl, CO2CH3, methoxy or ethosy When Ar is phenyl then one or two substituent groups aie preferred Even more preferred substituents mclude ethyl, n-piopyl, iso-propyl, hydroxymethyl, hyaroxyethyl, thiomethyl, ammomethyl, bromo and CO2H Most preferred substituents are methyl, ethyl and hydruxyrnethyl
Suitably R1and R2 are mdependently selected from hydrogen, halogen, nitio, cyano, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, Y(CH2)pNR4R5 Y(CH2)pCONR4R5, Y(CH2)pCO2R6, Y(CH2)pOR6, Y(CH2)pR6. or R1 and R2 are linked together as -OCH2O- or -OCH2CH2O-Preferably R1 and R2 are hydrogen chloro, me±oxy, ethoxy, O(CH2)2NR4R5, 0(CH2)3NR4'R5 NH(CH2)2NR4R5 or NH(CH2)2NR4R5 where R4 and R54 are hydrogen or methyl or one is methyl and the other is pyridyl or R4 and R5 form a morpholine, 3,5 dimethylmorpbolme, thiomoipholme, pytrolidme, pipeiazine (optionally substituted), piperidine, tiiazole or imidazolyl ring, or R4 and R5 are independently 0(CH2)3C02CH3, O-
benzyl, I-beazyl-4-prendinylamino, O(CH2)2NMe2, OCH2CONH2,O(CH2)2NHMe, 0(CH2)3NH2, nitro or cyano, or R1 and R2 are linked together as -OCH2O- or -OCH2CH2O-
Where R4 and R5 form a 4- to 7-membered saturated or aromatic heterocycli ring system suitable examples of such rings include morpholine, 3,5 dimethylmorpholme, 2,6-dimethylmoiphohne, thromorpholme, pyrrolidine, prperrzme (optionally substituted by C1-C8 alkyl), pipendine, trrazole or imidazolyl
Where one of R4 and R5 is hydrogen or C1-C8 alkyl and the other is a 5- or 6-inembered heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, examples of such nngs include thienyl, furyl, pyrimidyl, imidazolyl, pyridyl and pyrazole
Most preferably R1 IS methoxy, ethoxy, OCH2CONH2, O(CH2)2OMe, O(CH2)3OH, 0(CH2)3CO2Me, O(CH2)2NR4R5, 0(CH2)3NR4R5 O(CH2)4NR4R5 where R4'and R5 are both hydrogen or methyl or together with the nitrogen lu which they are attached form a pipendme or morphohne nng, or R1 IS NH(CH2)3NR4'R5 where R4 and R5 together with the nitrogen to which they are attached form an imidazole ring
Most preferably R2 is methoxy, ethoxy, OCH2CONH2, O(CH2)2OMe, 0(CH2)3OH, 0(CH2)3CO2Me, O(CH2)2NR4R5, 0(CH2 O3NR4R5 or O(CH2)4NR4R5 where one of R4 or R5 is methyl and the other is pyndyl, or R4 and R5 are selected from hydrogen or methyl or together with the nitrogen to which they are attached form a thiomorpholine, pipendme, moipholine, imidazole, trazole or 2,6-dimethylmorholine group
Most preferred compounds are thobe wherein R1 and/or R are both methoxy or ethoxy, 01 one is methoxy and the other is ethoxy
Especially preferred compounds of the invention include those exemplified herein, both m free base form and as pharmaceutically accsptable salts
Compounds of the mvention can fonn pharmaceutically acceptable solvates and salts The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochlonc, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, inandelic, taitanc, tnfluoroacetic and inethanesulphomc acids
The invention also provides a method of treating or prevenling a disease mediated by JAK3 which comprises administering to a mammal a compound of formula (1) as defined above
(Formula Removed) in a further aspect the inventLon provides a compound of formula (I) as deflned above but excluding the compounds 4 (2-bromoamhno) 6,7-d}methoxy 3-quznohnecarboxanude and 4-(l,S-dichloroanilino)-6,7-dunethoxy-3-quinolinecarboxamide for use in therapy,
Certain compounds of formula (I) are believed to be novel and therefore all novel compounds form a further aspect of the mvention 1 he invention therefore provides a compound of formula (lA.) (Formula Removed)
in which
Ar is phenyl substituted by ethyl, piopyl, hydrox3anethyl or CO2H or disubstrituted by methyl and hydroxymethyl,
R' IS methoxy. ethoxy or a group OCH2CONH2. OCH2CH2OCH3, or 0(CH3)pR4 R5where p IS 2 or 3 and R4 and R5 are hydrogen, methyl, ethyl 01 propyl or together R4 and R5 form a pyrrohdine, imidazole or moipholine rmg,
R2 IS methoxy, ethoxy or 0(CH2)pNR4R5 where p is 2, 3 or 4 and R4 and R5 are hydrogen, methyl or ethyl or one of R^ or R' IS methyl and the other is pyridyl or pyrazole or R4 and R^ form a pipendme, hydroxypipendme, thtomoipholine, moipholine, pyrrolidine, 2,6-dimethylmorpholme imidazole or tnazole nng,
or d pharmaceutically acceptable salt or solvate thereof,
provided that when A is phenyl substituted by ethyl or propyl or disubstituted by methyl, then R1 and R2 are not both methoxy, R1 and R2 are not both ethoxy or one of R1/R2 IS not methoxy when the other is ethoxy
Pieferred compounds of formula (lA) are those novel compounds exemplified herein
4-(2-ethylanilino)-6-methoxy-7-{2-[methyl(4-pyndinyl)amino]ethoxy}-3-
quinoiinecarboxamide.
4-[3-(hydroxymethyl)-2-methylamino]-6-methoxy-7-[3-(4-thioinorpholinyl)propoxy]-3-quinolinecarboxamide,
4-[3 -(hydroxymethyl)-2-methylamino] -6-methoxy-7-[3-(1 -prperidinyl)propoxy]-3-quinolinecarboxamide
4-[3-(hydroxymethyl)-2-methylamino]-6-methoxy-7-[3-(4-morpholiny])propoxy]-3-quinolinecarboxamide,
7-[3-(dimethylamino)propoxy]-4-(2-ethylamino)-6-methoxy-3-quinolinecarboxamide, 7-[3-(dimethylamino)propoxy]-4-[3-(hydroxymethyl)-2-methylamino]-6-methoxy-3-quinolinecarboxamide
7- {3-[(2R,6S)-2,6-dimethylmorpholinyl]propoxy}4-[3 -(hydroxymethyl)-2-methylamino]-6-methoxy-3-quinolinecarboxamide,
4-(2-ethylamino)-6-methoxy-7-[3-(4-niorpholiny]Jpropoxy]-3-quinolinecarboxamide, 4-(2-ethylamino)-6-methoxy-7-[4-(4-morepholinyl)butoxy]-3-quinolinecarboxamide, 4-(2-ethylamino)-6-methoxy-7-{3-[methyl(4-pyndinyI)aniino]propoxy}-3-quinolinecarboxamide,
4-(2-ethylamino)-7-methoxy-6-[2-(methyldmino)etboxy] 3-quinolinecarboxamide, 7- {3-[(2S,6S)-2,6-dimelhyImorpholinyl]propoxy}-4-[3-(nydroxymethyl)-2 methylamino]-6-methoxy-3-quinolinecarboxamide,
4-(2-ethylamino)-7-[3-(lH-imiddzo]-l-yl)propoxy]-6-methoxy-3-quinolinecarboxamidee, 6-(2-aminoethoxy)-4-(2-ediyldndino)-7-methoxy-3-quinolinecarboxamide, 6-methoxy-4-[2-(methylsulfanyl)amino]-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarboxamide,
6-methoxy-7-[3-(4-morpholinyl)propoxy] 4-(2-tolurdino-3-quinolinecarboxamide, 4-(2-ethylamino)-6-methoxy-7-[3-(1H-1,2,4-tridzol-l-yl)propoxy]-3-quinolmecarboxamide,
4-(2-ethylamino)-6-methoxy-7-[2-(methy amino)ethoxy] 3-quinolinecarboxamide, 4-(2-ediylamino)-6-inethoxy-7-(2-methoxyethoxy)-3-quinolinecarboxamide, 4-(2-ethylamino)-7-(3-hydroxypropoxy)-t)-methoxy-3-quinolinecarboxamide, 6-methoxy-7-[2-(4-morpholmyl)ethoxy]-4 (2-tolurdino)-3-quinolinecarboxamide, 4-[3-(hydroxzymethyl)-2-methylamiono]-7-methoxy-6-[2-(1-pyrrlidiny])ethoxy]-3-quinolinecarboxamide
3 - {[3 -(aminocarbonyl)-6,7-dimethoxy-4-quinolinyl]amino} -2-methylbenzoic dcid, 4-[3-(hydio\ymethy])-2-inethylani]ino]-b,7-dimethoxy-3-quinolinecarboxdmide, 4-(2-ethylamino)-7-[2-(IH-imidazol-l-yI)ethoxy]-6-methoxy-3-qquinolinecarboxamide, 4-[3-(2-hydroxyethy])-2-inethyIanihno]-6,7-dimethoxy-J-quinolinecarboxamide, 7-methoxy-6- {[2-(4-morpholiny])ethyl] amino} -4-(2-tolurdino)-3-quinolinecarboxamide, 4-(2-ethylamino)-6-[3-(lH-imidazol-l-yl)propoxy]-7-methoxy-3-quinolinecarboxamide, 4-(2-ethylamino)-7-methoxy-6-[2-(l-pyrrolidiny)ethoxy]-3-quinolinecarboxamide,
7-(3-aminopropoxy)-4-(2-ethylamlino)-o-methoxy-3-qumolinecarboxamide, methyl 4-{[3-(aminocarbonyl)-6-methoxy-4 (2-toluidino)-7-quinohnyl]oxy}butanoate, 4-[3-(aminomethyl)2-methylanilino]-6,7-dimethoxy-3-quinolinecarboxamide, 6-{[3-(1H-imidazol-l-yl)propyl]amino}-7-methoxy-4-(2-tolurdino)-3-quinohnecarboxamide,
4-[3-(hydroxymethyl)-2-methylaminonilino]-7-methoxy-6-(2-mcthoxyethoxy)-3-qumohnecarboxamide,
6-[2-(dimethylamino)ethoxy]-4-(2-ethylamino)-7-methoxy 3-quinolinecarboxamide, 4-[3-(cyanomethyl)-2-methylanilino]-6,7-dimethoxy-3-quinolinecarboxdmide, 4 [3-(2-amino-2-oxoethy])-2-methylamino]-6,7-dimethoxy 3-quimolmecarboxamide, 6-(3-aminopropoxy)-4-(2-ethylanilmo)-7-methoxy-3-quuiolinecarboxdamide, 4-[3-(hydroxymethyl)-2-methylanilmo]-7-methoxy-o-[3-(4-morpholmyl)propoxyj-3-quinolinecarboxamide,
4-[3-(hydroxymethyl)-2-methylamiono]-7-methoxy-6-[2-(4-moipholinyl)ethoxy]-3-quinolinecarboxamide, and pharmaceutically acceptable salts thereof
Further novel compounds of furmula (lA) include those of examples 186 217
Compounds of the present invention include all stereorsomerb, pure and mixed racemates, and mixtures thereof Tautomers of compounds of formula ([) and (lA) also form an aspect of the invention
In a further aspect the invention provides a proccess for the preparation of a compound of
formula (I) which comprises
(a) reaction of a compound of formula (II) (Formula Removed)
in which R1 and R2 are as defined m formula (I) or are protected derivatives thereof and R20 is a leaving group, with a compound of formula (III)
(Formula Removed)in which .Ar and R are as defined in formula (I) or are protected derivatives thereof, or (b) tor compounds ot formula (I) where R1 and/or R2 are groups Y(CH2)pNR4'R5 Y(CH2)pC0NRV, Y(CH2)pC02R6 Y(CH2)pOR' or Y(CH2)pR' where Y is oxygen, reaction of a compound of formula (IV)
(Formula Removed)where the R1 or R2 to be converted mto a group Y(CH2)pNR4R5, Y(CH2)pCONR4'R5 Y(CH2)pCO2R', Y(CH2)pOR6 or Y(CH2)pR6 is hydroxy and the other R1 or R2 together with Ar are as defined above tor process (a) with a compound of fonnula (V)
(Formula Removed)where R21 is NR4R5 CONR4R5 COZR6 OR6 or R6and R4 R5 and R6 are as defined m fonnula (I) or are protected denvatives theieof,
and optionally thereafter process (a) or (b)
• removing any protecting groups
. convert a compound of formula (I) into a further compound of formula (1)
• forming a pharmaceutically acceptable salt
In process (a) the group R20is a leaving group such as halogen, in particular chloro The reaction can be earned out in an inert solvent such as DMF at elevated temperature, for example at about 100°C
In process (b) the leavmg group L is preferably halogen, in particular chloio The reaction can be earned out m the presence of a base such as cesium carbonate in an mert solvent such as DMF or ethanol
Compounds of fomiula (II) can be prepared by reacting ccunpounds ot formula (VI)
(Formula Removed)in which R1 R2 and R20 are as defined in formula (II) with a chlonnatmg agent such as diionyl chloride, and reaction of the correspondmg acid chloride with ammonia
Compounds of formula (VI) can be prepared usmg literature chemistry
It will be appreciated that certam functional groups may need to be protected usmg standard protectmg groups The protection and deprotection of functional groups is for example, described m 'Protective Groups m Organic Chemistry', edited by J W F McOmie, Plenum Press (1973), and 'Protective Groups m Organic Synthesis', 3rd edition, T W Gieene &P G M Wuts, Wiley-Intertence(1999)
Diseases mediated by JAK3 mclude inflammatory, immunological, and bronchopulmonary disorders
The present invention also relates to a pharmarceutical composition for (a) treatmg or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arlhntis, psonasis. Type I diabetes and Lomplicatioiis from diabetes, cancer, asthma, rhinitis, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia, and other autoimmune diseases or (b) the inhibition of protein tyrosine kmases or Janus kmase 3 (JAK3) m a mammal, mcluding a human, i,ompnsing an amount of a compound of fonnula I oi a pharmaceutically acceptable salt thereof, effective in such disorders or conditions and a pharmaceutically acccptable carrier
Preferably the compoundit of the mvention are used for the treatment of asthma, rheumatoid arthritis, and host versus graft rejeclion/transplantation
The present invention also relates to a pharmaceutical composition for (aj treating or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthiitis, psoriasis. Type I diabetes and acomplications from diabetes, cane, asthma, rhmitis, atopic dermatitis, autoimmune thyroid disordeis, ulcerative colitis,
Crohn's disease, Alzheimer's disease, leukemia, and other autoimmune diseases or (b) the inhibition of protein tyrosme kinases or Janus kinase 3 (1\K3) m a mammal, mcludmg a human, compnsing an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, alone or m combmation with a T-cell immunosuppresant or antiinflammatory agents, effective in such disorders or conditions and a pharmaceutically acceptable earner
The present mvention also relates to a method for the inhibition of protein tyrosine kinases or Janus Kinase 3 (JAK3) m a mammal, mcluding human, compnsmg admmistenng to said mammal an effective amount of a compound of foimula I or a pharmaceutically acceptable salt thereof
In a still further aspect the mvention provides the use of a compound of formula (lA) as a therapeutic agent
The dose of the compound to be admmistered will depend on the relevant mdication, the age, weight and sex of the patient and may be detemuned by a physician The dosage will preferably be m the range of from 0 1 mg/kg to 100 mg/kg
The compounds may be administered topically, e g to the lung and/or the airways, in the form of solutions, suspensions, HFA aerosols oi dry powder formulations, e g. formulations in the mlialer device known as the Turbuhaler , or systemically, e g by oral administration m the form of tablets, pills, capsules, syrups, powders or granules, or by parenteial administration, e g in the form of stenle parenteral solutions or suspensions, or by rectal administiation, e g in the form of suppositunes
The compounds of the mvention may be administered on their own or as a pharmaceutical composition compnsmg the compound of tlie invention in combination with a pharmaceutically acceptable diluent, adjuvant or earner Particulaily pieferred are compositions not contammg matenal capable of causing an adverse, e g an allergic, reaction
Dry powder formulations and pressunzed HFA aerosols of the compounds of the mvention may be administered by oral or nasal inhalation For inhalation the compound is desirably finely divided The finely divided compound preferably has a mass median diameter of less than 10 fiin, and may be suspended m a propellant niixtuie with the assistance of a dispersant, such as a C8-C20 fatty acid or salt thereof, (e g oleic acid), a bile salt, a phospholipid, an alkyl sacchande, a perfluorinated or poiyethoxylated surfactant, or other
pharmaceutically acceptable dispersant
The compounds of the invention may also be administered by means of a dry powder inhaler The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler
One possibility is to mix the finely divided compound with a earner substance, e g a mono-, dx- or polysaccharide, a sugar alcohol, or an other polyol Suitable earners are sugars, e g lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, and starch Alternatively the finely divided compound may be coated by another substance The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound
Another possibility is to process the finely divided powder into spheres which break up durmg the inhalation procedure This spheroiiized powdei may be filled into the drug reservoir of a multidose inhaler, e g. that known as the Turbuhaler in which a dosmg unit meters the desired dose which is then inhaled by the patient With this system the active compound, with or without a earner substance, is delivered to the patient
FOI oral administration the active compound may be admixed with au adjuvant or a carrier, e g lactose, saccharose, sorbitol, mannitol, a starch, e g potato staich, corn starch or amylopectm, a cellulose derivative, a binder, e g gelatine or polyvinylpyrrolidone, and/or a lubncant, e g magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets If coated tablets are required, the cores, prepared as described above, may be coated with a concentiated sugar solution which may contain e g gum arable, gelatine, talcum, titanium dioxide, and the like Alternatively, the tablet may be coated with a suitable polymer dissolved in a leadily volatile oiganic solvent
For the preparation of soft gelatine capsules, the compound may be admixed with e g a vegetable oil oi polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets Also hquid or semisolid formulations of the drug may be filled into hard gelatine capsules
Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol Optionally such liquid preparations may contain colouring agents, flavounng agents, saccharine and/oi carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art
The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions
The term 'medical therapy' as used herein is intended lo include prophylactic, diagnostic and therapeutic regimens earned out m vivo or ex vivo on humans or other mammals
The following Examples illustrate the mvention
General methods Ail reactions were perfomied m dried glassware m an argon atmosphere at room temperature, unless otherwise noted All solvents and reagents and solvents were used as received Merck Silica gel 60 (0 040-0 063 mm) was used for preparative silica gel chromatography A Kromasil KR-100-5-C18 column (250 x 20 mm, Akzo Nobel) and mixtures of acetonitnle/water at a flow rate of 10 ml/min was used for preparative HPLC. Reactions were monitored at 254 nm by analytical HPLC, using a Kromasil C-18 column (150 X 4 6 mm) and a gradient (containing 01% trifluoroacetic acid) of 5 to 100% of acetonitrile m water at a flow rate of 1 ml/mm Evaporations of solvents were performed under reduced pressure usmg a rotaiy evapoiator dt a maximum tcunperdture of 40'C Products were dned under reduced piessure at 40 °C
'H-NMR spectra were recorded on a Vanan Inova-400 or Unity-5004 instrument The central solvent peak of chloroforra-d (δH 7 27 ppra), dimethylsulfoxide-d6 (δH 2 50 ppm) or methanol (δH 3 35 ppm) were used as mtemal references Low resolution mass spectra obtained on a Hewlett Packard 1100 LC-MS system equipped with a APCI lonisation chamber
Merck Silica gel 60 (0 040-0 063 mm) was used foi preparanvc silica gd chiomatography. A Kiomasil KR-100-5-C18 column (250 x 20 mm, Akzo Nobel) and mixtures of acetonitnle/water at a flow rate of 10 ml/mm was used for prepaiative HPLC Reactions were monitored at 254 nm by analytical HPLC, using a Kromasil C-18 column (150 x 4 6 mm) and a gradient (contaming 0 1% trifluoioacetic acid) of 5 to 100% of acetonitrile m water at a flow rate of 1 ml/mm. Evaporations of solvent!) were peiformed under reduced pressure using a rotary evaporator at a maximum tempeiature of 40 "C Products were dned under reduced pressure at 40 °C Example 6-(Benzyloxy)-4-13-(hydrorymethyl)-2-methylamino]-7-methoxy-3-guinolinecarboxamide a) l-(Benzyloxy)-2-methoxy-4-nitrobenzene 4-Nitroguaiacol potassium salt monobydrate (2S g, 111 mmol) and cesium carbonate (3 25 g, 10 mmol) were transferred into a 500 ml one-neck flask and dry dimethylformamide (200 ml) was added, benzyl bromide (21 4 g, 125 mmol) was added dropwise at roomtemperature under N2 atmosphere and the reaction mixmre was stirred vigorously for about 3 hours The solvent and the excess of benzylbiomide were tlien removed under reduced pressure Water (200 ml) and ethanol (100 ml) was added to the crude product and refluxed for 10-15 mmutes The yellowish crystalls were filtered from the cold mixture, washed with water and dried to give 29 g (100% yield) of the title compound 1H NMR (CDCI3) δ 7 85 (IH. dd), 7 77 (IH. d), 7 46-7 32 (5H, m). 5 26 (2H. s). 3 97 (3H, s) b) 4-(Benz}loxy)-3-methoxyanihne. To 1 (Benzyloxy)-2-melhoxy 4-nitrobenzene (26 g, 100 mmol) dissolved in ethanol (500 ml) m a 2 hire one-neck flask was added dropwise under 30 minutes a solution af sodium dithionite m water (500 ml), stirnng was continued at ambient temperature for 2h and after that the reaction mixture was heated at 70-80°C for approx 4h, cooled and alkalized with sodium carbonate The precipitate was filtered, washed with water and dned Ihe combined water phases were extracted with ethylacetate The combined organic phases were washed with water, dned over sodium sulfate, filtered and cvapoiated to drynness The residue was combined with the filtered precipitate to afford 9 3 g (41% yield) of the product 1H NMR (DMSO-d6) δ 7 42-7 24 (5H, m). 6 67 (IH, dj, 6 2 ' (IH, d). 6 02 (IH. dd), 4 86 (2H, s), 4 68 (2H, s). 3 67 (3H. s) c) Diethyl 2-(4-benzyloxy-3-niethoxyanmino)methylenemaloiiate A mixture of 4-(Benzyloxy)-3-methoxyaniline (9 3 g. 40 mmol) and diethyl ethoxymethylenemalonate (9 65 g. 45 mmol) were heated at 120°C for 1-1 5h, the ethanol produced was removed under reduced piessure, affording 16 g (100% yield) of the title compound
1H NMR (CDCl3) δ 110 (IH, d). 8 43 (IH, d) 7 45-7 29 (5H m), 6 87 (IH, d), 6 67 (IH,
d). 6 64 (IH, dd), 5 14 (2H, s). 4 31 (2H, q). 25 (2H. q), 3 91 (3H, s), 1 39 (3H, t), 1 32
C3H,t)
d) Ethyl 6-benzyloxy-4-chloro-7-methoxy-3-quinolinecarboxylate
A mixture of diethyl 2-(4-(benzyloxy-3-methoxyanilmo)methylenemalonatB (16 g, 40
mmol), toluene (100 ml) and phosphorus oxychlonde (25 ml) was heated to reflux under
nitrogen atmosphere for 5 hours After coolmg, the solution was evaporated to remove the
solvents and excess of phosphorus oxychlonde The residue was treated with aqueous
sodium bicarbonate, water and some ethanol, heated to reflux for some mmutes After
coolmg the precipitate was filtered, washed three times with water and dned m vacuum at
50°C to afford 12 g (81% yield) of the title compound
1H NMR (DMS0-d6) δ 8.97 (IH, s), 7 68 (IH, s), 7 55 (2H, bd), 7 53 (IH, s), 7 46-7 35
(3H, m), 5 34 (2H, s), 4 40 (211. q), 4 00 (3H, s), I 37 (3H, t)
e) 6-(BenzyIoxy)-4-chloro-7-methoxy-3-quinolinecarboxylic acid
Ethyl 6-(Beiizyloxy)-4-chloro-7-methoxy-3-quinolinecarboxylate (11 9 g, 32 mmol) was dissolved in a mixture of tetrabydrofliiane (THF) and methanol (300 ml) m a ratio of 1 1 Aqueous sodium hydroxide (2 0 M, 65 ml, 130 mmol) was added and the mixture stured at room temperature for 2 hourb The organic. bolvents were removed by rotatory evaporation and the resulting solution diluted with moie water (200 ml) cooled on ice and acidified to pH 2-3 with hydrochlonc acid under vigorous stimng The precipitate was filtered off washed twice with water, twice with ethanol and ether and finally dned m vacuum at 50°C over night to give a white solid, 11 0 g (I00°/o yield)
1HNMR (DMS0-d6) δ 13 66(IH. bs), 8 97 (HI, s), 7 68 flPI, b), 7 54 (2H, bd), 7 52 (IH, s), 7 46-7 34 (3H, m), 5 34 (2H, s), 4 00 (3H, s)
f) 6-(VenzyIoxy)-4-i:hloru-7-methoxy-3-quinoIiiiecarbo camide
A mixture of 6-Benzyloxy-4-chloro-7-methoxy-3-quinolinecarboxylic acid (II 0 g, 32
mmul), thionyl chlonde (30 ml) and toluene (100 ml) was refluxed for 2 hoars under N2
atmosphere
After cooling toluene and the excess thionyl chlonde was lemovcd by rotatory evaporation
and the residue was suspended m acetone (250 ml) and the resulting suspension cooled in
an ice-bath Aqueous ammonia (25%, 20 ml) was added gradually, keeping the temperatuie
below l0°C Stimng was continued for 3 houis and the auetone was then removed by
rotatory evaporation The residue was suspended in watei (200 nil) and stured for one hour,
filtered off, washed twice with water, twice with ethanol and ether and finally dned m
vacuum at 50'C over night to give a ofEwhite solid, 10 4 g (95% yield)
1H NMR (DMS0-d6) δ 8 65 (IH. s), 8 10 (IH. s), 7 83 (JH, s), 7 59 (IH, s), 7 54 (2H,
bd), 7 50 (IH, s)i 7 46-7 34 (3H, mj, 5.33 (2H, s), 3 98 (JH, s)
g) 6-Benzylovy-4-3-(hydroxymethyl-2-methylamino)-7-methoxy-3-qumolinecarboxamide. A mixture of 6-Benzyloxy-4-chloio-7-methoxy-3-quinohnecaiboxamide (1 72 g, 3 mmol), 3-ammo-2-methylbenzylalcohol (.0 82 g, 6 mmol), acetic acid (1 2 ml) m DMF (20 ml) was heated at l00°C fox two hours After coohng the reaction mixture was poured on ice-water (SCO ml) and alkalized to pH 9 with dilute sodium hydroxide The resulting precipitate was filtered oft, washed with water, air dned, washed twice with ether and tiien dned tn vacuum at 50°L to gi\e2 15 g (97% yield) of the title compound as a white solid
1H NMR (CDCls) δ 10 82 (IH, s). 8 87 (IH s), 8 26 (IH, s), 7 59 (IH. s). 7 37-7 20 (5H, m), 7 14-7 04 {3H. m), 6 73 (IH, s), 6 65 (III, d), 5 22 (IH, t), 4 61 (2n, d), 4 50 (2H, s), 3 91 (3H, s), 2 20 (3H. s)
Example 2
6-Hydroxy-4-3-(hydroxymethyl-2-methylanilino)-7-methoxy-3-quinolinecarboxaamide
A mixture of 6-Benzyloxy-4-3-(hydroxymethyl-2-methylanilino) 7-methoxy-3-quinolinecarboxamide (2 1g, 4 7 mmol) and 10% palladium on caibon (0 44 g) in methanol (50 ml), DMF (40 ml), ethylacetate (40 ml) and acetic acid (0 5 ml; was hydrogenolyzed at atmospheiic pressure at 25°C Alter 24 hourst the reaction mixture was filteied through a plug of celite, which was subsequently washed with DMf The combined filtrates were alcalized with aqueous ammonia was added and tlie solvents were lemoved by reduced pressure The lesidue was suspended m methanol (10 ml), filtered and washed with methanol and ether, dried in vacuum at 50°C overnight to give 1 1 g (66% yield) of the title compound as a yellow solid
1H NMR (DMSO-d6) δ 10 43 (IH. s), 9 53 (IH, s), 8 8i (IH, s), S 27 (IH, s), 7 60 (IH, s), 7 27 (IH, s), 7 08 (IH, d), 6 95 (IH, t). 6 75 (IH, s), 6 40 (IH, d), 5 13 (HI, t), 4 57 (2H. d), 3 92 (3n, s), 2 29 (111. t,)
fcxample 3
4-(3-Hydroxymethyl-2-methylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-3-quinolinecarboxmide
A mixture of 6-hydroxy-4-(3-hydroxymethyl-2 methyamino-7-methoxy-3 quinohneoarboxamide (0 071 g, 0 20 mmol), 4-(3-chloiopropyl)morpholine (0 036 g, 0 22 mmol), cesiumcarbonate (0 13 g, 0 40 mmol) and DMF (2 5 ml) was heated at 100'C for two houib After cooling the reaction mixture was poured on water and extracted three times with dichloiomethane, the solvents were removed by leduced pressure and the
residue was chromatographed on silica using dichloromethane'methanol/ammunia
(200 10 1) as eluent
Fractions containing the product (slightly impure) were combined and evaporated The
lesidue was triturated with the eluent affording 40 mg (38% yield) of the title compound as
a white solid
1H NMR (CDCI3) δ 10 91 (IH. s), 8 76 (IH. s). 7 26 (IH. s). 7 16 (IH.dd). 7 14 (IH. t).
7 04 (in, dd), 6 74 (IH, s). 6 15 (211, bs 4 69 (2IJ, hi.), 3 95 (3H, s), 3 79 (4H, bt). 3 54
(2H. bt), 3 49 (IH, s). 2 46 (4H. m). 2 32 (2H, m), 2 30 (3H, s.). 1 63 (2H, qvj
Example 4
4-(3-Hydroxymethyl-2-methylamino-7-methoxy-6-(2-methoxyethoxy)-3-quino]mecarboxamide
prepared according to the method described in Example, 3
1H NMR (DMS0-d6) δ 10 81 (IH, t.). 8 87 (IH, s), 8 26 (IH, sj, 7 59 (IH, s), 7 25 (IH, sj. 7 19 (IH, d). 7 07 (IH. t). 6 67 (IH, d). b 65 (IH. s), 5 15 (IH. t), 4 56 (2n. d), 3 89 (3H, s). 3 47 (2H. bt), 3 40 (2H, bt), 3 20 (311, i). 2 26 (311 s)
Example 5
4-(3-Hydroxymethyl-2-methylamino-7 methoxy-6 acryloxyloxy-3-quinulinecurboxniide
prepdied according to the method described m Example 3
1H NMR (DMSO-d6) δ 10 89 (IH. s). 8 86 (111. s). 8 25 (IH. i). 7 56 (IH. s). 7 22 (HI. s), 7 18 (IH. d), 7 07 (IH, t), 6 70 (IH, d), 6 65 (IH, i), 5 14 (III, t). 4 55 (2H. d), 3 88 (3H, s). 3 32 (2H, bt), 2 24 (3H, s). 1 45 (2H. m), 1 JJ 1 15 (lOH, m), 0 87 (3H. t)
Example 6
4-(3-hydroxymethyl-2-methylniliiiu)-7-methoxy-6-[2-(4-merpholinyll)ethoxyl]-3-quinolinecarboxamide
prepared according to the method described in Exmple 3
1H NMR (DMS0-d6) δ 10 86 (IH. s.). S 8 7 (IH, b). g J6 (IH. hrs). " 59 (IH. brs). 7 24 (IH, s), 7 18 (IH. d) , 7 07 (IH, t) 6 68 (1H, d), 6 67 (IH, s), 5 15 (IH, t), 4 55 (2H, d) , 3 88 (3JI. s). 3 54 (4H. m) . 3 45 (2H. brt). 2 43 (2H, t). 2 30 (4H, m), 2 24 (3H, s)
Example 7
4-(3-hydroxymethayl-2-methylamino)-7-methoxy-6-(2-(l-piperidinyl)ethoxy]-3-quinoliaecarboxamide
prepared according to the method described in Example 3
1H NMR (DMS0-d6) δ 10 84 (IH. s) . 8 86 (IH, s), 8 25 (iH. brs) . 7 57 (IH. brs), 7 22 (IH, s), 7 17 (IH. d), 7 05 (IH. t), 6 67 (IH. d), 6 65 (IH, s), 5 13 (IH, brs) , 4 54 (2H. s). 3.86 (3H. s), 3 41 (2H, brt) , 2 39 (2H, t), 2 25 (4H. ni) . 2 23 (3H. s) . 1 45 (4H, m). 1 35 (2H. m)
Example 8
4-(3-hydroxymethyl-2-methylamino)-7-methoxy-6-[2-(l-pyrrolidinyl)ethoxy]-3-
qulnolinecarboxamide
prepared according to the method descnbed in Example 3
1H NMR (DMS0d6) δ 10.83 (IH. s) . 8 87 (HI. s) , 8 26 (IH, brj.) , 7 58 {IH, brs) , 7 24
(IH, s). 7 IS (IH, d) , 7 06 (IH. t), 6 67 (IH, s). 6.6o (1H. d). 5 16 (IH. brt), 4.55 (2H,
d), 3 88 (311, s), 3 44 (2H, brt), 2 51 (211, m i, 2 35 (4H, m), 2.26 (3H, s), 1 65 (4H, m)
Example 9
6-I2-(dimethylamino)ethoxy]--4-(3-(hydroxymethyl-2-melhylaniliuo)-7-metlioxy-3-quinohnecarboxamidc
prepared according to the method descnbed in Example 3
1H NMR (DMS0-d6) δ 10 87 (IH. s) , 8 88 (IH, s). 8 27 (IH. brs) . 7 60 (IH, brs). 7 26 (IH, s), 7 19 (IH, d), 7 08 (lU, t), 6 69 (IH. d). 6 68 (IH, s), 5 14 (HI, brs), 4 56 (2H, s), 3 89 (3H, s). 3 51 (2H, brt) , 2 62 (2H, bit), 2 26 (6H, s), 2 25 (3H, b)
Example 10
6-(2-(dzniethylamino)-2-oxoethoxy]-l-(3-hydroxymelhyl-2-metliylanilino)-7-methoxy-3-qiiinohnecarboxamide
prepared according to the method described m Example 3
1H NMR DMS0(d6) δ 10 81 (IH. s) , 8 89 (IH. s) . 8 28 (IH. brs). 7 60 (JH, brs), 7.27 (IH, s), 7 17 (IH. d), 7 03 (IH, t), 6 58 (IH. d) . 6 48 (IH. s), 5 18 (IH. brt) , 4 57 (2H. d). 4 23 (2H, brs) . 3 91 (3H. s) . 2 74 (3H. s). 2 66 t3H. s) , 2 22 (3H. s)
Example 11
6-(2-amino-2-oxoethoxy)-4-(3-hydroxymethyl-2-methylamino)-7-methoxy-3-quinolmecarboxamide
prepaied according to the method desLnbed in bxdiuple 3
'HNMRDMS0(d6) 5 10 71 (IH, s) , 8 88 (HI, sj. 8 26 (IH, brs) , 7 59 (IH. brs). 7 27 (111, s), 7 26 (IH. s). 7 18 (IH, d), 7 05 (IH, s), 7 OJ (IH, tj, 6 62 (IH, s.) . 6 58 (IH. d) ,5 l[ (IH, t) , 4 57 (2H, d) . 3 91 i.3H, s) , 3 85 t2H, !,J . 2 26 (3H, s)
Example 12 4-(2-Ethylamino)-6-methoxy-7-[3-(4-morphohnyl)propoxyl-3-quinolmecarboxamide
a) 4-Chloro-7-hydroxy-6-methoxy-3-quinolmecarboxamide.
A mixture of 7-Benzyloxy-4-chloro-6-methoxy-3 quinolmecarboxamide (1 0 g, 2 9 mmol) prepared analogous to the method described in Example 1 and thioanisole(1 75 ml. 14 1 mmol) in IFA (15 ml) was refluxed for three hours After cooling, the inlvenls were removed at reduced pressure and the residue was poured on water and alkalized with aqueous ammount The precipitate was filtered, washed with water and dried affording 0 52 g (72% yield) of the title compound
b)4-(2-Ethylanihno)-6-methoxy-7-[3-(4-morpholinyl)propoxl-3-quinolmecarboxamide.
A mixture of 4-Chloro 7-hydroxy 6 methoxy-3-quinolmecarboxamide (0 056 g, 0 22 mmol), 2-ethyldnihne (32 µl, 0 2b mmol) and acetic acid (10 µL) in ethanol (5 ml) was heated at reflux for tour hours. The solvents were removed by reduced pressure, and the residue was chromdtographed on silica using methano! as cluent The product was dissolved in DMSO (5 ml), morpholinopropylchloride (.0 018 g. 0 11 mmol) and CS2CO1 (0 090 g. 0 28 mmol) were added and the mixture was heated at 100°C tor 20 hours Alter cooling the mixture was poured on water and the water phases were extracted with methylenechlonde The residue was cluomatographed on silica using methylnechlonde/methanol (9/1-1/1) as eluent, affording 9 mg {9% yreld) of the titled compound 'HNMR (CDCI3) δ 11 05 (IH. s). 8 9o (IH. s). 735 (ill. s), 7 32 (IH. dd). 7 12 (2H, m), 6 91 (IH. dd). 6 74 (IH, s), 4 22 (211, in), 3 bi. (4H, in), 3 25 (3H, s). 2 80 (2H, m). 2 52 (2H. q). 2 44 (4H, m), 2 08 (2H. ni), 1 30 (3il. t)
the title compounds of examples 13-1:) were prepared by a method analogous to that described in Example 12
Example 13
6-Methoxy-4-(2-(methylsulfanyl)amino-7-[3-(4-morpliolinyl)propoxy]-3-quinolinecarboxamide.
1H NMR (CDCI3) δ 10 76 (IH. s), 8.89 (IH, s), 7 34 (IH, b). 7 32 (IH. d), 7 11 (IH, dd), 7 02 (IH, dd). 6 79 (IH, d),6 75 (IH, s),4 21 (2H. t), 3 72 (4H, 0, 3 39 (3H, s), 2 55-2 42 (6H, m). 2 49 (3H, s). 2 10-2 02 (2H. m)
Example 14
4-[3-(Hydroxymethyl)-2-methylanilino]-6-methoxy-7-[3-(4-morpholiayl)propoxy]-3-quinolinecarboxamide.
1H NMR (CDCI3) δ 10 81 (IH. s), 8 79 (IH, i). 7 26 (IH, s), 7 20 (IH. d). 7 16 (IH. dd), 6 84 (IH, d). 6 69 (IH, s). 4 74 (2H, s), 4 15 (2H, t), 3 6S (4H. t), 3 29 (3H, s), 2 48 (2H, t), 2 42 (4H. m), 2 32 (3H. s), 2 01 (2H. m)
Example 15
4-(1H-lndol-4-ylamino)-6-methoxy-7-[3-(4 morpholiny)propxy]-3-
quinolmecarboxamide.
1H NMR (CD3OD) δ 8 82 (HI, s), 7 37 (IH. d), 7 23 (IH, d). 7 15 (IH. s). 7 14 (IH, t),
6 92 (III. s). 6 88 (IH. d). 6 2] (IH. d\ 4 21 (2H, t), 3 78 (4H, t), 2 98 (3H, s). 2 98-2 88
(6H, mj, 2 18 (2H,m)
Fxdmple 16
Methyl-l-{[3-(ammocarbonyl)-6-methoxy-4-(2-toludino)-7-quiuolinyl]oxy}butanoate.
A mixture of 7-hydroxy-6-methoxy-4-(2-tolurdino)-3-quinolmecarboxamide (0 026 g,
0 080 mmol), DMSO (2 5 ml), K2CO3 (0 017 g, 0 12 mmol). and methyl 4-chlorobutanoate
(0 01 Ig, 0 080mmol) was refluxed for 2h The reactionmixruie was, filtered, evaporated
and chromatographed on silica furnishing the title compound
1H-NMR DMS0-d6 δ 10 72 (IH, s). 8 85 (IH, s), 8 25 (IH, bn,); 7 58 (IH, brs), 7 28 (IH,
d). 7 22 (IH. s). 7 10 - 6 97 (2H. m), 6 68 (IH, d), 6 67 (IH, s). 4 10 (2H,t), 3 57 (3H, s),
3 26 (3H, sj. 3 28 (3PI, s) 2 05-1 93 (4H, m)
APCI-MS m/z 424 I LMH+]
Example 17
4-(2-Ethylamino)-7-(3-hydroxypropory)-6-methoxy-3-quinolinecarboxamide. A mixture of 4-(2-ethyldnilmo)-7 hydroxy-6-methoxy-3-quinolinecarboxamide (0 12 g,
0 35 mmol), DMSO (15 ml), CS2CO3 (0 34 g, 1 0 mmolj, and 1,3-dibromopiopane was
stirred at 100°C for 2h The reaction mixture was pouied out on NaHC03(aq) and extracted
with CH2CI2 The substance was chromatogiaphed on furnishing the title compound (0 012
g, 9%)
1H NMR (CDCI3) δ 10 82 (IH. s), 8 83 (IH, s.), 7 34-/ 26 (2H. m). 7 09 (IH, m), 6 83 (IH, dd), 6 70 (IH, s), 4 60 (2H, 0, 3 93 (2H, t), 3 28 (UI, s), 2 77 (2H,q). 2 12 (2H, m),
1 22 (3H, t)
APCI-MS m/z 396 1 [MH+]
Example 18
6-Methoxy-7-[2-(4-morpholinyl)ethoxy] 4-(2-tolurdino)-3-quinohnecarboxamide.
The title compound was piepaied according to the method desciibed m Example 12
1H NMR (CDCl3) δ 10 60 (III. s). 8 72 (IH, s). 7 28-7 26 (2H. m). 7 07 (IH. m). 6 89
(IH, m), 6 75 (IH, i), 4 28 (211, t). 3 72 (4H, t). 3 32 (3J1, s), 2 hi, (3H,t), 2 58 (4H, t), 2 36
(311. s)
APCI-MS m/z 437 2 [MH+]
Example 19
4-(2-Ethylamido)-6-methoxy-7-(2-methoxyethoxy)-3-quinolinecarbuxamide.
A mixture of 4-(2-ethylanmino)-7-hydroxy 6-methoxy 3 quinolmecarboxamide (0 22 g,
0 65 mmol), DMF(15 ml). CS2CO3 (0 64 g. 1 98 mmol), and 2-bromoethylmethylether was
stirred at 100°C for 2h The reaclionmixturr was evaporated and chromatugraphed on
furnishing the title compound (0 045 g,18%)
1H NMR (CDCI3) δ 10 70 (IH, s), 8 72 (IH. s), 7 30 (111, dd), 7 26 (IH, s), 7 08 (IH, m)
6 85 (IH, dd), 6 74 (H, s), 4 28 (2H. t) 3 83 (2H, t). 3 45 (3H.s), 3 30 (3H, &). 2 80 (2H.
q). I 30 (311. t)
APCI MS m/z 396 1 [MH+] Example 20 4-(2-Ethylanilino)-6-methoxy-7-[3-(lH-l,2,4-triazol-l-yl)propoxyl-3-quinolinecarboxamide a) Ethyl 3-(lH-l,2,4-triazol-l-yl)propanoate. To a solution of lH-l,2,4-triazole (5g, 72 4 mmol), EtOH (36 ml) and Na (1 66 g, 72 4 mmol) ethyl-3-bromopropronat (9 9 ml, 79 6 mmol) was added dropwise The reaction muture was stirred ovemight, filtered, evaporated to 50 ml and distilled furnishing the title compound (3 3 g 30%) as a white solid 1H NMR (DMSO-d6) δ 8 43 (IH, s), 7 90 (IH. s), 4 30 (2H, t). 3 94 (2H, q), 178 (2H, t). 1 05 (3H. t) b) 3-(lH-l,2,4-triazoI-l-yl)-l-propanol. To a solution ot Ethyl 3-(lH-l,2,4-tndzol-l-yljpropanoate (2 95 g, 17 5 mmol) m ether (90 ml), L1AIH4 (0 66 g, 17 5 mmolj was added After healing to reflux for 60h, 10 ml of 50%-methdnol-water was added The reaction mixture was filtered and the filter washed with 100 ml of methanol and twice with 100 ml of hot water After evaporation the title product was obtained after punfication using preparative IIPLC 1H NMR (CDCI3) δ 8 42 (IH, s), 7 98 (IH, s), 4 35 (IH. t). J 47 (2H. t), 2 09 (.211, q) c) l-(3-ChloropropyI)-lH-l,2,4-triazole. 3-(lH-l,2,4-trizol-l-yI)-l-propanol (0 160g,
1 3 mmol) was refluxed in thionylchlonde (3 ml) lor 2 h The rccation mixture was
evaporated yielding the title product APCI-MS m/z 146 1 [MH+] d) 4-(2-Ethylamino)-6-methoxy-7-[3-(1H-l, 2,-4-trizol-l-yl)propoxy]-3-
quiuolinecarboxamide. The title product was prepared according to the method described m Example 17 1HNMR (CDC13)- δ 10 71 (IH, s), 8.70 (IH. si. 8 07 (IH. si. 7 94 (IH. s), 7 34-7 29 (IH. m), 7 20 (IH, s), 7 16-7 05 (2H, m). 6 90-6 85 (IH, m), 6 76 (IH, s), 4 44 (2PI.t). 4 28 (2H. t). 3 62 (3H, s), 2 80 (2H. q), 2 46 (2H, m), 1 30 (3H, t) APCI-MS m/z 447 5 [MH+] Example 21 4 -(2-Ethylamino)-6-methoxy'-7-[4-(4-morpholnyl)butoxy]-3-quinohnecarboxainide. 4-(2-Ethylamino)-7-hydroxy-6-methoxy 3-quinohnecaraoxamide (0 064 g, 0 19 mmol) was dissolved in DMSO (4 ml), l-bromo-4-chlorobutane (22 µl, 0 19 mmol) and CS2CO3 (0 18 g, 0 55 mmo]) were added and the mixture was stirred at ambient temperature for three days 1 he mixture was poured into watei and extracted with methylenechlonde The residue was cbromatographed on silica using etbylacetate/methanol (1 0->l 1) as eluent The resulting oil was dissolved m DME, morpboline (25 |il, 0 29 mmol) and a catalytic ammount of KI was added, mixture was heated at reflux fur four days After cooling the mixture was poured out on water and extracted with methylenechlonde The crude product was purified on preparative IIPLC, affording 20 mg (22% yield) of the titled compound 'HNMR(CDCI3) 5 1131 (IH. s). 9 02 (IH, s). 7 40 (III, s), 7 34 (IH. d), 7 22-7 11 (2H, m), 6 95 (IH, d), 6 73 (IH. s), 4 18 (2H. t), 3 72 (4H, m), 3 29 fJH, s), 2 79 (2H, q), 2 5-2 40 (6H, m), 1 93 (2H, m), 1 69 (2H, m), 1 28 (3H, t) Example 22 a) 7-(3-Chloropropoxy)-4-[3-(hydroxmethyl)-2-methtlamino]-6-methoxy-3-quinolinecarboxamide. 7-Hydioxy-4-[3-(hydroxyniethyl)-2-methylamino]-6 methoxy 3-quinoliuci.drboxamide (0 90 mg, 2 54 inmul) was dissolved in DMF (10 ml), 1 bromo 4 chlorobutane (0 28 ml, 2 79 mmol) and Cs2CO3 (1 7 g, 5 2 mmol) were added and the mixture was stirred at ambient temperature for three days The mixture was ponied out on water and extracted with methylenechlonde The residue was chromatographed on silica using ethylacetate/methanol (1 0->5. I) as. eluent, affording 550 mg (50"6 yield) of die titled compound H NMR (DMSO-d6) δ 10 85 (IH, s), 8 83 (IH, s), h 22 (IH, s,br), 7 30 (IH, s,br). 722 (IH, s), 7 10 (IH, d), 7 02 OH, t), 6 65 (lit, d), 6 62 (.111. si, 5 18 (.HI, m), 4 58 i2H, d), 4 21 (2H, t), 3 78 (2H, t), 3 22 (3H, s), 2 25 (311, s), 2 2J-2 19 (211, m) Example 23 a. 23 b 7-{3-|(cts)-2,6-Dimethylmorpholinyl]propoxy}-4-[3-(hydroxymethyl)-2-methylanilino]-6-metho\y-3-quino]lnecai boxamide and 7-{3-|(trans)-2,6-Dimethylmorpliolinyl]propoxy}-4-[3-(liydro\ymethy0-2-methylanilno]-6-methoxy-3-quinoinecar boxamide 7-( l-chloropropuxy)-4-[3-(hydroxymethyl)-2-methylamin]-6-methoxy-3-quinolinecarboxamide (50 mg, 0 12 mmol) was dissolved m DME (3ml). 2,6-dimerhylmorpholine (25 µ1, 0 29mmo]) and a catalyric ammount of KI added, the mixture was heated at reflux for four days After cooling the mixture was filtrated and the crude product as purified on preparati ve IIPLC, affording 14 mg (23% yield) of the cis- compound and 8 rag (13% yield) of the trans-compound 7-{3-[(cis)-2,6-dimethylmorpholinyl]propoxy}-4-[3-(hydroxymethyl)-2-methylamlino]-6-methoxy-3-quinolinecarboxanude s1H NMR (CD3OD) δ 8.89 (IH. s), 7 24 (IH. d), 7 20 (III, s). 7 18 (IH. tj, 6 95 (IH, d), 6 79 (IH, s), 4 68 (2H, s), 4 20 (2H, t), 3 75-3 65 (2H, m), 3 29 (3H, s), 3 0 (2H, d), 2 78 (2H, t), 2 38 (3H, s), 2 16 (2H, m), 1 95 (2H, m), 118 (6H. d)
7-{3-[(trans)-2,6-dimethylmoipholmy]]propoxy}-4-[3-(bydroxymethyl)-2-methylanilmo]-6-metlioxy-3-quinolinecarboxdmide
1H NMR CD3OD, at 55'C" 5 8 82 (IH, s), 7 52 (IH. d), 7 33 (IH, t). 7 29 (IH, s;, 7 18 (IH, d), 6 85 (IH, s), 4 78 (2H. s), 4 30 (2H, t). 4 18 (2H, m). 3 35 (3H, sj, 3 21 (4H, m). 2 93 (2H, m), 2 34 (2H. rn), 2 35 (3H, s). 1 35 (6H. d)
the title compounds of example 24-26 were prepaied by a method analogous to that descnbed in Example 23
Example 24
4-[3-(Hydroxymethyl)-2-methylamino]-6-methoxy-7-[3-(l-pipendinyl)propoxy]-3-quinolinecarboxamide
1H NMR (CD3OD) δ 8.82 (IH, s), 7 34 (IH, d), 7 25 (IH, s), 7 18 (IH, t). d 89 (IH, d); 6 85 (111, s), 4 75 (211, s), 4 22 (2H, t), 3 35 (JH, S), 3 20-3 05 (6H, m). 2 40 (3H, i,); 2.28 (2H, ni), I 85 (4H, m), 1 64 (2H, m)
Examnle 25
7-{3-I(2-Ethoxyethyl)amino]propoxy}-4-[3-(hydroxymethyl)-2-methylamino]-6-methoxy-3-quinolinecarboxamide.
1HNMR (CD3OD) δ 8 82 (IH, s), 7 30 (111, d), 7 25 (IH,:,). 7 18 (IH, tJ, 6 89 (IH, d), 6 82 (IH, s). 4 76 (211. s), 4 22 (2H, t). 3 59 (211, t). 3 53 (211. q). 3 35 (3H. s), 2 89 (2H, t), 2 83 (2H, t), 2 40 (3H, s), 2 12 (2H. m), 1 18 (3H. t)
Example 26
4-[3-(Hydroxymethy])-2-methylamino]-6-methoxy-7-[3-(4-thiomorpholinyl)propoxy]-3-quinolinecarboxamide.
1H NMR CD3OD) δ 8 81 (IH. s). 7 31 (IH, d). "^2: ( II. &) 7 18 (.IH. t), 6 86 (IH, d). 6 80 (IH. s), 4 75 (2H, s), 4 20 (2H, tJ, 5 38 (311, s), 3 08 (211 m), 2 8U-2 60 (811, m), 1 39 (3H, ), 2 08 (2H, m)
Example 27
6-[3-(Dimethylanuno)propoxy]-4-(2-ethylamino-7-methoxy-3-quinolinccarboxamide
a) 6-(Benzyloxy)-4-(2-ethylamino)-7-methoxy-3-quinolinecarboxamide
The title compound was prepared according to the method described in Example 1g APCl-MS m/z 428 [MH+]
b) 4-(2-Exthylamino)-6-hydroxy-7-methoxy-3-quinolmecarboxamide
The title compound was prepared according to tbe method described in Example 2 1H NMR(DMS0-d6) δ 10 52 (III. s), 9 54 (III, brs,). 8 86 (111, sj. 8 29 (IH.brs), 7 62 (III, bra), 7 28 (]H, i), 7 28 (111, m). 6 98 (211, m,, 6 6 (IH b), 6 45 (111. m), 3 92 (311. s). 2 75 (211. q), 129(311.1) APCl MS m/z 338[MH+]
c) 6-[3-(Dimethylamino)propoxyl-4-(2-ethyamino)-7-methoxy-3-quinolinecarboxamide
Polymer-bound Triphenylphosphme (0 15 g, 0 44 minol) and 3 dimethylamino l-propanol (26µl 0 22 inmol) was suspended and disolved in ( H C 12 and THF at 15°C and stirred for 30 ram DEAD (70 µl, 0 44 mmol; was added dropwise at -15"C 4-(2-Ethylamino)-6-hydrooxy-7-methoxy 3 quin linecarboxamide (50 mg, 0 15 mmol) was suspended m TIIF and then added to the reaction The reaction was stured over night, allowing the tempeuture rise to -10"f The polymer was filtered off and the filtrate concentrated in vacuo The product was purified using preparative HPLC affording 15 mg (24%) of white crystals
1HNMR (CD3OD;δ 8/9 (IH, s), 7 37 (111, m). 7 22 (IIJ. s), 7 15 (2H, in), 6 84 (IH, m). 6 78 (IH, s), 3 95 (3H. s), 3 42 (Hi, t), 2 JO (2H, q.), 2 35 (2H, t), 2 23 (bU, s) 1 74 (2H. m). 1 29 (3H, t) APCI-MS m/z 423 [MH+J
the title compounds of examples 28-33 were prepared by a method analogous to that descnbed in Example 27
Example 28
4-(2-Ethylamino)-6-[3-(lH-imidazol-yl)propoxyl-7-methoxy-3-
quinolinecarboxamide
1H NMR (CD3OD) δ 8 80 (IH. s), 7 54 (IH, s), 7 29 UH, m), 7 24 (IH, s), 7 06 (3H. m),
6 98 (IH, s), 6 80 (IH, m), 6 71 (IH, s), 3 99 (3H, s). 3 28 (2H, m), 2 75 (2H, q), 2 04 (2n,
m). 1 27 (3H, t)
APCI-MS m/z 446 [MH+]
Example 29
4-(2-Ethylamino)-7-methoxy-6-(3-thienylmethoxy)-3-quinolinecarboxamide
1H NMR (CD3OD) δ 8 80 (IH, s), 7 J7 (2H. m), 7 24 (IH s), 7 16 (2H, m^, 7 06 (IH, m),
6 91 (IH, m). 6 87 (IH, s), 6 83 (IH, m), 4 53 (2H, s), 3 97 (3H, s), 2 76 (2H, q). 1 29 (3H,
0
AJPCI-MS m/z 434 [MH+]
Example 30
6-[2-(Dimethylamino)ethoxyl-4-(2-ethylamino)-7-methoxy-3-quinolinecarboxamide 1HNMR (CD3OD) δ 8 80 (]H, s), 7 37 (IH, m), 7 22 (III, i). 7 15 (2H, m). 6 84 (IH, ra), 6 78 (IH, m), 3 95 (3H, s), 3 50 (2H, brt), 2 80 (2H, q), 2 57 (2H, t). 2 24 (611, s), 1 30 (3H. t) APCI-MS m/z 409 [MH+]
Example 31
6-(3-Aminopropoxy)-4-(2-ethylamino)-7-methoxy-3-quinolinecarboxamide
The compound was synthesized as above, using 60c amino protected alcohol After
flitenng off the polymer and evaporation, the residue was dissolved in CII2CI2 and TFA
(50 50) and stirred at room temperature for 30 nun The solvent was evaporatsd and the
product was purified by preparative HPLC
1H NMR (CD3OD) δ 8 82 (IH, s), 7 38 (IH, m), 7 23 (IH, s), 7 16 (211, m), 0 86 (IH, m).
6 80 (IH, s), 3 97 (3H, s). 3 48 (2H. brt), 2 81 (2H, q), 2 71 (2H, t), 1 74 (2H. in), 1 31
(3H, t)
APCI-MS m/z 395 [MH+]
Example 32
4-(2-Ethylamnio)-7-methoxy-6-[2-(methylamiino)ethoxy]-3-quinolinecarboxamide 'H NMR (CDjUD) 6 8 80 (IH,:,), 1 36 (\Yi, m), 123 (]1I, b), 1 \5 (2H. m), 6 84 (HI, m), 6 80 (Hi, s), 3 97 (3H. s), 3 50 (2H, brt), 2 79 (2H. qj 2 75 (2H, t), 2 37 (3H, s), 1 29 (SH,
t)
APCI-MS m/z 395[MH+]
Example 33
6-(2-Aminoethoxy)-4-(2-ethylamino)-7-methoxy-3-quinolinecarboxamide 1H NMR (CD3OD) δ 8 80 (IH, s), 7 36 (IH, brd). 7 11 (IH. i). 7 14 (2H. m), 6 84 (HI, brd), 6 78 (IH, s). i 96 (3H. s), 3 41 (2H. brt), 2 79 (411, ni), 1 29 (3H, I) APCI-MS m/z 381 [MH+]
Example 31
7-[3-(Dimethylamino)propoxy]-4-(2-ethylamino)-6-methoxy-3-quinolinecarboxamide
a) 4-(2-Ethylamino)-7-bezyloxy-6-methoxy-3-quinolinecarboxamide
The title compound was prepared as debcribed m Example 27a starting from 7 benzyloxy-
4 cliloro 6 methoxy 3-quinolinecarboxamide prepared dnalugouii to the method descnbed
in Example 1 Yield 4 4 g (89 %) of a light brown powder
1H NMR (DMS0-d6) δ 11 85 (IH, brs), 8 98 (IH, s), 8 47 (III, bn,), 7 84 (IH, brs), 7 52-
7 33 (7H, m), 7 29-7 17 (2H. m). 6 99 (IH brd), 6 IS (HI. i). 5 26 (2H, h). 3 24 (3H. s),
2 70 (2H, q), 1 20 (3H. t)
APCI MS m/z 428 [MH+]
b) 4-(2-Ethylamino) 7-hydroxy-6-methoxy-3-quinolinecarboxamide
The title compound was prepared as described in Example 27b
Yield 0 3 g (90%) of a yellow oil that crystallizes after a tew hours
1H NMR (CD3OD) δ 8 70 (IH, s), 7 39 (IH, ni), 7 19 (JH, m), 7 00 (HI, s), 6 94 (IH, m),
6 73 (IH. s). 2 78 (2H, q), 1 29 (3H, t)
APCI NS m/z 338 [MH+]
c) 7-[3-(Dimethylamino)propoxy]-4-(2-ethylamino)-6 methoxy-3-quinohnecat boxamide
The title compound was prepared as described m Example 27c
1H NMR (CD3OD) δ 8 78 (IH, s), 7 35 (IH, m), 7 19 (IH, s), 7 13 (211, m), 6 83 (IH, m). 6 77 (IH, s). 4 15 (2H, t), 3 28 (3H. s), 2 79 (2H, q), 2 57 (IH, t), 2 29 (6H, s), 2 05 (2H, m), 1 28 (3H. t) APCI-MS m/z 423 [MH+]
the title compounds of examples 35-37 were prepared by method analogous to that described in Example 34
Example 35
4-(2-Ethylamnio)-6-methoxy-7-{3-[methyl(4-pyridinyl)amino]propoxy}-3-quinolinecarboxamide
1H NMR (CD3OD) δ 8 78 (IH, s), 7 93 (2H, brm), 7 37 (IH, m). 7 16 (211, mj, 7 13 (IH, s) 6 84 (IH, m), 6 79 (IH, s). 6 67 (2H, brdj, 4 12 (2H, t), 3 65 (2H, tj, 3 33 (JH, s), 3 01 (3H, s). 2 80 (2H. q). 2 13 (2H. m), 1 31 (3H. t) APCI-MSm/z 486 [MH+]
Example 36
4-(2-£lhylanilino)-6-methoxy-7-{2-[methyl(4-pyridinyl)amino]ethoxy}-3-quinolinecarboxamide
1HNMR(CDCl3) δ 11 (lH,s), 8 88(1H, .), 8 20 (2H, br.J. 7 SJ (Hi, d), 7 32 (IH, &), 7 15 (2H, m;. 6 90 (IH, d), 6 75 (111, d), 6 M (III, i), 4 36 (211. tl, 3 94 (.211, t), 3 23 (3H, s). 3 19 (311. s), 2 78 (2H, q). 1 29 (311, t) APCI MS m/z 472 [MH+]
Example 37
4-(2-Ethylamino)-6-methoxy-7-[2-(methylamino)ethoxyl-3-quinolinecarboxamide 1H NMR (CD3OD) δ 8 80 (IH, &), 7 37 (IH, m). 7 23 (IH, s), 7 15 (2H, m), 6 8b (IH, m), 6 80 (IH, s) 4 24 (2H, t), 3 30 (3H, s), 3 04 (211, t) 2 80 (211 qj, 2 47 (3H s). 1 29 (3H, t) APCI-MS m/z 395 [MH+]
Example 38
4-(2-Ethylamino)-6-methoxy-7-[2-(l-prperazinyl)ethoxyl-3 quinolinecarboxamide Triphenylphosphine (0 12 g, 0 44 mmol) and l-(2 hydroxyethyl)prperazme (25µl, 0 22 mmol) was, dissloved m CH2CI2 and THF at 15°C and stirred for 30 mm DEAD (70 µl,
0 44 ramolj was added dropwise at -15°C 4-(2-ethylamino)-7-hydioxy-t)-methoxy-3-
quinolmecarboxamide (0 50 g, 0 15 mmol) was suspended in THE and then added to the
reaction The reaction was stined over night, allowing the temperature rise to ~10'"C The
solvent was removed under reduced pressure and the product was punfied using
preparative HPLC affording 34 mg (24%) of a clear oil
1H NMR (CD3OD) δ 8 80 (IH, s). 7 36 (IH. m), 121 (IH, s), 7 13 (2H. mj, 6 83 (III, m),
6 77 (IH, s), 4 28 (2H, t), 3 28 (3H. s), 2 86 (6H. in). 2 79 (2H, q), 2 62 (4H, brs), 1 29
(iH, i)
APCI-MSin/z 450 [MH+]
the title compounds ot examples 39-41 were prepared by a method analogous to that described in Example 38
Example 39
4-(2-Ethylanaino)-7-[3-(1H-wnidazol-l-yl)propoxyl-6-methoxy-3-
quinolinecarboxamide
1H NMR (CD3OD) δ 8 79 (IH, s), 7 64 (IH. s), 7 37 (1H, m). 1 15 (311. m), 6 95 (IH, s6 84 (in. m). 6 79 (IH. s). 4 26 (2H. t), 4 06 (211, t), 3 } I (3H. sy. 2 80 (2H, q), 2 32 (2H.
m), 1 29 (3H. t)
APCI-MS m/z 446 [MH+]
Examnle 40
4-(2-Ethylamino)-7-[2-(lH-indazol]-l-yl)ethoxy]-6-methoxy-3-quinouccarboxnide 1H NMR(CDaOD) δ 8 78 (IH, s;, 7 75 (IH, s), 7 3o (IH. in). 7 25 (IH, s;, 7 17 (IH, s), 7 13 (2n, m;, 6 93 (IH, s), 6 83 (HI, m), 0 78 (HI. s), 4 48 (2H, I). 4 36 (211, t), 3 29 (311. s), 2 78 (211, Li), 1 28 (3H, t; APCi-MS m/z 432 [Mm |
Example 41
7-(3-Aminopropoxy)-4-(2-ethylamino)-6-methoxy-3-quinolinecarboxamide
The compound was synthesized as above, using Boc-amino protected alcohol After filtering off the polymer and evaporation, the residue was dissolved m CH2Cl2 and TFA (50 50) and stirred at room temperature for 30 mm The solvent was evaporated and the product was punfied byprepaiative HPLC
'H NMR (CD3OD)δ879(IH,s),736 (IH. m),720(1H, s),713(2H,ra),683(IH, m). 6 77 (IH,s),421 2H, t).328(3H, s),288(2H.t),279(2H,q),203(2H. m),129(3H,
t)
APCI-MS m/z 395 [MH+]
Example 42
7-Hydroxy-4-(3-(hydroxymethyl)-2-methylamino]-6-methoxy-3-quinolinecarboxamide
The title compound was prepared accordmg 10 the method debcribed in Example 34b 1H NMR (DMS0-d6) δ 10 86 (IH. s), 8 81 | IH, s), 8 21 (IH, brs), 7 54 (IH, brs), 7 18 (IH, d), 7 12 (IH, s), 7 08 (IH, t), 6 69 (IH, d). 6 65 (IH, s), 5 14 (IH, brsj, 4 56 (2H. s), 3 25 (3H. s), 2 25 (3H, s) APCI-MS m/z 354 [MHi-]
Example 43
6-{[3-(lH-imidazol-l-yl)propyl]amino}-7-methoxy-4-(2-toluidino)-3-quinohnccarbo\amJde
a) Ethyl 4-Chlor 0-6-bromo-7-methoxy-3-quinolinecarboxamide
The title compound were prepared essentially as, described by Bmke et dl J Med Ckem, 36(1993)425-432
b) Ethyl 6-bromo-7-methoxy-4-(2-toluidino )-3-quinolinecarboxamide
Ethyl 6-bromo-4-chloro-7-methoxy-3-quinolinecarboxamide (0 90 g, 2 6 ramol), o-toluidme (0 30 ml, 2 9 mmol) and AcOH (1 ml) was dissolved m EtOH (50 ml) and refluxed for 4 his After cooling the mixture was neutralised with aqueous ammonid and the precipitate was filtered off affording 870 mg (80%) of a green powder
1H NMR (DMS0-d6) δ 9 84 (IH, s), S 94 (IH, s), 7 89 (IH, ,), 7 41 (III, s), 7 i6 (IH, brd), 7 16 (2H, m), 6 94 (IH. brd). 4 15 (2H, q). 3 99 (iH, 5), 2 28 (3H, s), 1 26 (3H t)
c)6-{[3-(lff-imida20l-l-yI)propyl]amino}-7-methoxy-4-(2-toluidino)-3-quinolinecarboxamide
A mixture of 6-bromoqmnohne (0 25 mmol), Pd2(dba)3 (0 005 mmol), BINAP (0 015 mmol), CS2CO3 (0 33 mmol) and I-(3-am]nopropyl)-imidazolb (0.29 mmol) was stirred at 90°C over night under N2 After cooling the mature was punfied by flash silica gel column
chrumatography Elution with CII2CI2 and then CH2Cl2MeOIl (10 1) gave 110 mg (10u%) of a yellow oil which contained minor phosphine impurities APCI-MS m/z 460 [MH+]
The crude ethylester was hydrolysed m MeOII/5M NaOH (1 1) at r t over night After concentrating in vacuo, the remaning aqueous phase was made acidic with 2M HCl and washed with CH2CI2 The aqueous phase was .neutralised with 5M Na2C03 and extracted with CHCI3 Concentrating m vacuo gave 25 mg (25%) of a yellow oil APCI-MS ra/z 432 [MHt-]
The crude acid (0 025 g. 0 06 mmol) and CDl (0 020 g, 0 I mniul) was dissolved m DMF and stirred at 60°C for 1 h The mixture was cooled in a EtOH/dry ice bath and saturated ■with 'NH3(g) and then stirred at room temperature for 45 minutes The mixture was diluted with CHCl3, washed with saturated aqueous NaHCO3 and water and concentrated m vacuo Purification with preparative HPLC gave after removal of the trifluoroacetic aceate salt 15 mg (60%) of a white solid
1H NMR (CD3OD) δ 8 67 (IH, s), 7 56 (IH. s. hn), 7 17 (IH. brdj. 7 1J (IH, s), 7 02 (IH, s, Im), 6 97 (IH, s, ha). 6 95 (2n, m), 6 68 (IH. brd), 6 2:5 (HI. s), 3 99 (3H, s), 3 90 (2PI. t), 2 67 (2H. t), 2 36 (3H, s), 1 68 (2H. in) APCI-MS m/z 431 [MH+]
the title compounds of example!) 44 46 were prepared by a method analogous to that desscribed in Example 43
Example 44
7-Methoxy-b-[(2-methoxyethyl)amino]-4-(2-tuluidin(i)- 3 quinolinecarboxamide 1H NMR (CD3OD) δ 8 66 (IH, s), 7 31 (IH, m), 7 11 (IH, t.), 7 10 (2H, m), 6 81 (IH, m). 6 34 (111, b), 4 00 (3H, s), 3 27 (311, s), 3 2 4 (2H, t), 2 7/ (2H, t), 2 J5 (JII, s) APCI-MS m/z 381[MH+]
Example 45
7-Melho\y-6-{[2-(4-moipholinyl)etliyl]amiiio}-4-{2-tolmdino)-3-quinulinecdrboiamide
1H NMR (DMS0-d6] δ 10 41 (IH, t), 5 M (IH. s), H 2i (lil, bibj. 7 56 (IH, bis), 7 23 (IH. d), 7 17 (IH. s). 6 96 (2H. m), 6 50 (HI, s). 6 22 (III, d), 5 43 (IH. t), 3 95 (3H, s), 3 42 (4H, brt), 2 71 (2H. q), 2 33 (311, s), 2 19 (6H, m)
APCI-MS m/z 436 [MH+]
Example 46
7-Methoxy-6-{[3-(4-morpholinyl)propyl]amino)-4-(2-tolurdino)-3-
quinolinecarboxamide
1H NMR (CD3OD)- δ 8 65 (IH, s); 7 27 (IH, brd), 7 11 (IH, s), 7 03 (2H, m), 6 72 (IH,
brd), 6 32 (IH. s), 3 99 (3H, s), 3 69 (4H, t), 2 68 (2H, t), 2 39 (4H, brm), 2.37 (3H, s),
2 27 (2H. t). 1 49 (2H, m)
APCI-MS m/z 450 [MH+]
Example 47
6-Methoxy-7-{[2-(4-morpholinyl)ethyl]amino-4-(2-toluidino)-3-quinolinecarboxamide
a) Ethyl 4-Chloro-7-bromo-6-methoxy-3-quinolinecarboxamide
The title compound were prepared essentially as described by Buike et al J Med Chem, 36(1993)425-432
b) Ethyl 7-bromo-6-methoxy-4-(2-toluidino)-3-quinolinecarboxamide
The title compound was prepared accoiding to the method descnbed in Example 43b 1HNMR (DMS0-d6) δ 9 S3 {IR, s), 8 S7 (IH, s.J, 8 15 (IIJ, s), 7 3S (lU, m), 7 17 (2H, m), 7 09 (IH. s), 6 98 (IH, m), 4.17 (2H, q), 3 45 (3H. s), 2.30 (311, s), 1 28 (3H, t)
c)6-Methoxy-7-{[2-(4-morpholinyl)ethyI]ammo}-4-c2-toIuidmo)-3-quinolinecarboxamide
The title compound was prepared according to the method de&cnbed m Example 43 c
'H NMR (CD3OD) 5 8 68 (IH, s), 7 28 (IH, brd), 7 06 (2H. inj, 6 81 (IH, brd), 6 73 (IH,
s), 6 60 (IH, s), 3 67 (4H, brt), 3 34 (2H, t), 3 33 (3H, s). 2 65 (2H, 1), 2 49 (4H, brt), 2 31
(3H.S)
APCI-MS m/z 436 [MH+]
the title compounds of examples 48-51 were prepared by a nierhod analogous to that descnbed m Example 47
Example 48
6-Methoxy-7-[(2-methoxyethyI)amino]-4-(2-toluidino)-3-quinolinecarboxamide
1HNMR (CDCh) δ 10 50 (IH, s), 8 73 (IH, s), 725 (IH, brd), 7 04 (2H, m;, 6 88 (IH, s), 6 87 (IH, brd), 6 63 (IH, s), 5 06 (IH, bitj, 3 66 (2H, tj, 3 42 (2H, q), 3 39 (3H, sj; 3 34 (3H, s). 2 37 (3H. s) APCT-MS m/z 381 [MH+]
Example 49
7-{ [3-( 1H-imidazol-l -yl)propyI] amino} -6-methoxy-4-(2-toluidino)-3-quinolinecarboxamide
1H NMR (CDCI3) δ 10 93 (IH, brs), 8 93 (IH, s), 7 51 (lU, s;, 7 27 (IH, bid), 7 09 (2H, ra), 7 06 (IH. s), 6 93 (IH, brd), 6 91 (HI, t,), 6 90 (IH, s). 6 62 (IH, s), 4 81 (IH, brt), 4 06 (2H, tj; 3 32 (3H, s), 3 25 (2H, ni), 2 35 (3H, s), 2 16 (2H, mj APCI-MS m/z 431 [MH+]
Example 50
7-[(l-Beiiz3i-4-piperidjnyl)ainino]-6-inetIiox]'-4-(2-toIuidin())-i-quinolinecarboxamide 1H NMR (CD3OD) δ 8 68 (IH, s), 7 32 ((.H, m), 7 09 (ill, m), 6 85 (ll-I, brd), 6 78 (III, s), 0 65 (IH, s), 3 59 (2H, b), 3 49 (IH, in), i 35 (3H, s),: 93 {IH, brd), 2 34 {ill, s), 2 28 (2H, brt), 2 08 (211, bid), 1 60 (2H, m) APCI-MS m/z 496 [MH+-]
Example 51
6-Methoxy-6-{[3-(4-morpholinyl)propy]amino}-4-(2 toludino)-3-
quinolinecarboxamide
1H NMR (CD3OD) δ 8 67 (IH. s), 7 31 (IH, brd), 7 11 (2H. m). 6 89 (IH, s), 6 70 (IH, s),
6 61 I IH, s). 4 84 (3H, s). 3 33 (3H, s), 3 30 (211. t), 2 49 (ill. t), 2 46 (4H, brt), 2 32 (311,
s), 1 87 (2U, m)
APCI-MS m/z 450 [MH+]
Example 52 4-[3-(HydroxymethyI)-2-methylanilino]-6,7-dimethoxy-3-quinulinecarboxamide
a) Ethyl 6,7-dimethaxy-4-chloro-3-quinolinecarboxylate
The title compound were prepared essentially as described by Burke el a1 J Med Chem, 36(1993)425-432
b) 6.7-Dimethoxy-4-chloro-3-qumolinecarboxamide
A mixture of ethyl 6.7-dimethoxy-4-chloro-3-quinoluiecaroxylate (3 0 g, 10 2 mmol) was dissolved in 40 ml methanol and NaOH(aq) (20 ml, 5M) The mixture was heated to 100°C for four hours After cooling the methanol was evaporated The water solution was acidfied with 2M HCl to pH 2-3 The white precipitate was cenfiuged and then decant This procedure was repeated twice The solid was dried m vacuum over night The solid was dissolved m 50 ml thronyl chlonde and heated to reflux for three hours After cooling the excess thronylchloride was removed by rotary evaporation and the residue was suspended in acetone, the resulting suspension was cooled in an ice-bath Ammonium hydroxide (7ml) was added, keeping the temperature below 0°C The suspension was stirred for 30 min and the resulting suspension was filtered off washed with water and air dried
1H NMll (DMS0-d6) δ 8.66 (HI, s). S.12 (IH, br sj. 7 87 (HI, br sj, 7 46 (2H, d), J 98 (3n,s),3 97(3H,s)
c) 4-(3-(HydroxymethyI)-2-mettiylanilinuJ-6,7-dimetlioxy-3-quinolinecarbuxamide. A
mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0 15 g, 0 56 mmol), 3-ammo-2-methyJbenzylalcohol (0 1 g, 0 73 mmol), acetic acid (0 2 ml) m EtOH (10 ml) was refluxed for 4h After cooling the pH was adjusted to 9 with aqueous NH3 The resulting precipitate was filtered off and washed with cold EtOH and dried in vaccum at 40'C to give 0 1 g (49% yield) of the title compound
1H NMR (DMS0-d6) δ 10 84 (IH, s), 8 83 (IH, s), 8 25 (IH. s), 7 56 (IH, s), 7 21 (IH, s), 7 17 (IH, d), 7 05 (IH, t), 6 17 (IH, d). 6 15 (JH, s), 5 12 (IH,brs), 4 52 (2H, s.), 3 87 (3H, s), 3 21 (3H, s), 2 23 (3H, s) APCI-MSm/z 368 2[MH+]
the title compounds of examples 53-56 were prepared by a method analogous to that described in Example 52
Example 53
4-(2-Bromoanilino)-6,7-dimethoxy-3-quinolinecarboxamide. 1H NMR (CDCI3] δ 10 28 (IH, s). 8 80 (IH, s). 7 63 (IH. d), 7 34 (IH, s), 7 21 (IH, s). 7 10 (IH. t), 7 05 (IH, t). 6 90 (IH, t), 6 75 (IH, s). 6 72 (lH,s), 4 0 (3H, s), 3 48 (3H, s) APCI-MS m/z 402 1, 404 1 [MH+]
Example 54
4-(4-Hydroxy-2-methy]amino)-6,7-Dmethoxy-3-quinolinecarboxamide. 1H NMR (DMS0-d6) 6 10 81 (IH, s), 9 30 (IH, s), 8 79 (IH, d), 8 18 (IH, brs), 7 45 (IH, brs), 7 19 (IH, s), 6 75-6 50 (4H, m), 3 84 (3H, sj, 3 26 (3H, s), 2 32 (3H. s) APCI-MS m/z 354 1 [MH+]
Example 55
6,7-Dimethoxy-4-(2-metItoxyandino)-3-quinolinecarboxamide
1HNMR (DMSO-d6) δ 10 41 (IH, s), 8 87 (IH, i), 8 13 (IH, s); 7 57 (IH.brs), 7 28 (IH, s), 7 09 (IH, dd), 7 03 (IH, dt), 6 83-6 78 (2H, m), 6 6^- (IH, brd), 3 91 (3H, s), 3 83 (3H,
s)
APCI-MS m/z 354 1 [MH+-]
Example 56
4-(4-Fluoro-2-methoylamino)-6,7-dimethoxy-3-quinolinecarboxamide. 1H NMR (DMS0-d6) δ 10 91 (IH, brs), 8 83 (IH, s), S 22 (IH. brs), 7 61 (IH. brs), 7 26 (IH. s). 7 23-6 93 (5H, m), 7 03 (IH, dt), 3 89 (JII, s). 3 37 (3H, s), 2 28 (3H,!,) APCI-MS m/z 356 2 [MHi-J
Example 57
4-[(l-Ethyl-lH-pyrazol-5-yl)amino]-6,7-dimethovy-3-quinolinecarboxamide A mixture of 4-chloro-6,7-dimethoxy-3-quinolmecarboxamide (0 046 g, 0 17 mmol), 1-ethyl-5-dminopyrazol (0 030 g, 0 27 mmol) and acelic acid (40 µl) in DMF (0 8 ml) was heated at 100 °C for 7 5 h The DMF was evaporated undei reduced pressure and the residue was dissolved in a mixture of MeCN and water (1 7) containing 0 1 % trifluoroacetio acid Preparative HPLC using a giadient ((containg 0 1 % tnfluoroacetic acid) of 10-»40 % MeCN in water as eluent gave, after evaporation, the title compound as
the tnfluoroacetic acid salt The product was suspended in saturated aqueous NaHCO3 and absorbed on a short SPE column [ISOLUTE™ C18 (EC)] pre-conditioned subsequently with methanol and water The column was washed extensively with water until the pH of the eluent was neutral The product was then eluted with methanol, the solvent evaporated and the residue crystallized from ethanol to give the title compound (19 mg, 32%) 1HNMR(DMS0-d6) δ II 09 (IH, bs). 8 88 (III, s), 8 34 (IH, bs), 7 71 (IH. bs). 7.42 (IH. d. / 1 4 Hz). 7 27 (IH, s), 6 67 (IH. s). 5 87 (IH, bs), 4 02 (2H, q, J7 2 Hz), 3.90 (3H. s). 3 46 (3H, s). 3 12 (3H, s) and 1 29 (3H. \.J11 Hz) APCI-MS m/z 342 1 [MH+]
Example 58
4-(3-Aniinocarboiiyl-2-inethyianiIino)-6,7-dimethoxy-3-(]uinolinecarboxamide
A mixture of 4-chloro-6,7-dimethoxy-3-quinohnecarboxamide (0 046 g. 0 17 mmol), 3-ammo 2-metylbenzamide (0 036 g, 0 24 mmol) and acetic acid (40 µl) m DMF (0 8 ml) was heated at 100 °C for 18 h After cooling the reaction mixture was diluted with water (20 ml) and made alkaline with 1 M NaOH The precipitate was filtered of. rmsed with water and dried to give the title compound (41 mg, 61%)
1HNMR (DMS0-d6) δ 10 76 (IH. s), 8 90 (IH, s). 8 30 (IH, bs), 7 75 (IH. bs). 7 64 (IH, bs), 7 44 (IH. bi), 7 28 (IH, s). 7 13-7 06 (2H, m), 6 75-6 45 (IH, m), 6 67 (IH, s). 3 90 (3H,s), 3 33 (3H, s) and 2 36 (3H. s) APCI-MS m/z 381 I [MH+]
Example 59
6,7-Dimethoxy 4-(2,3-diinethylaiiiIino)-3-qumolinecarboxamide
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g. 0 17 mmol), 2,3-
dimethylanilme (20 µl, 0 22 mmol) and acetic acid (40 µl) in DMF (0 8 ml) was heated at
100 °C for 3 5 h After cooling the reaction mixtur.e was diluted with water (15 ml) and
made alkaline with 1 M NaOH The precipitate was collected by filtration , iinsed with
water and dried to give the title compound (48 mg, 79%)
1H NMR (DMS0-d6) δ 10 87 (IH, s). 8 87 (1H,J,). 8 26 (IH, bs). 7 58 (IH. bs), 7 24 (IH,
s), 7 02-6 96 (IH. m). 6 98 (IH, s), 6 68 (IH. sj, 6 66-6 60 (IH. m). 3 88 (3H. s), 3 25 (3H,
s), 2 31(3H,s)and2 23(3H,s)
Example 65
4-(3-Hydroxy-2-methylamino)-6,7-dimethoxy-3-quiuolinecarboxamide
A mixture of 4-chloro-6,7-dimethoxy-3-qumolinecaibox amide (0 046 g, 0 17 mmol), 3-
amino-2-methylphenol (0 032 g, 0 26 mmol) and acetic acid (40 µl) m DMF (0 8 ml) was
heated at 100 °C for 1 5 h After cooling, the mixture was diluted with water (15 ml) and
made alkaline with saturated NaHCO3 The title compound, which slowly precipitated was
filtered off and dried to give 34 mg (55%)
1H NMR (DMS0-d6) δ 10 77 (IH, s), 9 49 (IH, s), 8 86 (IH, s), 8 25 (IH, bs), 7 58 (IH,
bs). 7 24 (IH. s), 6 88 (IH, 1,78 0 Hz). 6 76 (IH. b). 6 61 (III. d.y 8 0 Hz), 6 23 (IH, d. J
7 9 Hz), 3 89 (3H, s), 3 30 (3H, s) and 2 11 (311 si
APCl-MS m/z 354 1 [MH+]
Example 66
6,7-Dimethoxy-4-(3-methoxy-2-inelhylunilin())-3-quinulinecuiboxamide
A mixture of 4-chloio-6,7-dimethoxy-3-qumnolinecarboxamide (0 046 g, 0 17 mmol), 3-methoxy-2-methylanilmt (0 036 g, 0 26 mmol) and acetio acid (40 µl) in DMF (0 8 ml) was heated at 100 °C for 2 5 h After cooling, the mixture was diluted with water (15 ml) and made alkaline with saturated NaHCO3 The resulting gummy precopitate was colleoted and crystallized from methanol-water to give the title compound (45 mg, 70%) 1H NMR (DMS0-d6) δ 10 76 (IH, s), 8 87 (IH, s). 8 26 (IH, bb), 7 60 (IH, hi), 7 25 (IH, s), 7.05 (IH, t,y82Hz). 6 77 (IH, d,J8 2 Hz), 6 72 (HI, s). 6 36 (IH, d. J8 0 Hz), (3 89 (3H, s), 3 81 (3H s), 3 29 (3H. s) and 2 16 (3H, s) APCI-MS m/z 368 1 [MIH-]
Example 67
6,7-Dimethoxy-4-[(l-methyI-lH-indol-4-yl)amino]-3-qumolioecarboxamide
A mixture of 4-chloro-6,7-dimethoxy-3-quinolmecarboxamide (0 028 g, 0 10 mmol), 4-ammo-l-methyhndol hydrobhloride (0 026 g, 0 14 mmol) and sodium acetate (0 013 g, 0 16 mmol) m DMF (0 6 ml) was heated at 100 °C for 8 h After cooling, the mixture was diluted with water and made alkaline with saturated NaHCO3 The gummy precipitate was collected and crystallized from methanol-water to give the title compound (24 mg, 60%) 1H NMR (DMS0-d6) δ 11 07 (IH, s), 8 91 (IH. s), 8 28 (IH, bs), 7 61 (IH. bs), 7 27 (IH, d, y 3 2 Hz), 7 26 (IH, s), 7 20 (IH, d, J 8 2 Hz), 7 03 (IH, t, 77 9 Hz), 6 50 (IH, d, 77 4 Hz), 6 23 (IH, d, 73 1 Hz), 3 98 (3H, s). 3 79 (3H, s) and 3 12 (3H, b) APCI-MS m/z 377 1 [MH+]
Example 68
6,7-Dimethoxy-4-[(l-oxo-2,3-dihydro-lH-inden-4-yl)amino]-3-quinolinecarboxamide
A mixture of 4-chloro-6.7-dimethoxy-3-quuiolinecarboxamide (0 046 g, 0 17 mmol), 4-ammo-1-indanone (0 036 g, 0 24 mmol) and acetic acid (40 µI) m DMF (0 6 ml) was heated at 100 °C for I h 45 mm After cooling, the mixture was diluted with water and made alkaline with saturated NaHCO3 The precipitate was collected by filtration, washed with water and dried to give title compound (59 mg, 90%)
1H NMR (DMSO-d6) δ 10 60 (IH, s), 8 92 (IH, s). 8 30 (111, bs), 7 67 (IH, bs), 7 36 (IH, s), 7 32-7 25 (2H, m). 6 89 (IH, dd, J 6.(> and 2,0 Hz), 6 87 (IH s), 3 94 (3H, s), 3 42 (3H, s), 3 06-2 95 (2H, m) and 2 74-2 67 (211, in) APCI-MS m/z 378 1 [MH+]
Example 69
4-[l-Hydroxy-2,3-dzhydro-1H-inden-4-yI)amino-6,7-dimethoxy-3-quinolinecarboxamide
6,7-Dimethoxy-4-[(l-oxo-2,3-dihydro-lH'-inden-4-yI)ammo]-i-quinolinecarboxanude (0 062 g, 16 4 mmol) was dissolved m a mixture of methanol (7 ml), tetrahydrofiiran (4 ml) and water (3 ml) Sodium borohydride was added in portions (3x5 mg) and during 5 mm. After 20 mm the reaction mixture was acidified with acetic acid and then made alkaline with saturated aqueous sodium hydrogenoarbonate and evaporated The residue was partitioned between water and ethyl acetate The organic phase was washed twice with water and evaporated The residue was dissolved in methanol and water was added The title compound, which slowly precipitated, was filtered off and dried to give 40 mg (64%) 1H NMR (DMS0-d6)- δ 10 68 (IH, s), 8 82 (IH. sj. 8 20 (IH. bs), 7 55 (IH, bs), 7 22 (IH, s), 7 07 (IH. t, J 7 5 Hz). 7 04 (IH. f, J 7 4 Hz), 6 75 (IH, sj. 6 63 (IH. d. J 7 5 Hz), 5.20 (IH. d, J 5 7 Hz), 5 01 (IH, q, J 6 2 Hz), 3 85 (iH, s), 3 26 (s. moisture signal overlapping). 2 72-2 63 (IH, m), 2 50-2 36 (m, solvent signal overlapping), 2 30-2 20 (IH, m) and 1 76-1 65 (IH, m)
Example 70
4-(4-Carboxy-2-methylamino)-6,7-dimethoxy-3-quinolinecarboxamide A mixture of 4-chloro-6,7-dimethoxy-3-quinolmecarboxamide (0 046 g, 0 17 mmol). 4-ammo-2-methylbenzoic acid (0 036 g, 0 24 mmol) and acetic acid (40 µl) m DMF (0 8 ml) was heated at 100 "C for 12 h After cooling, the mixture was diluted with water (15 nil)
and made alkaline with saturated NaHCO3 and was then weakly acidified with acetic acid
The precipitate was filtered of and suspended m warm methanol After cooling, the
precipitate was filtered off and dried to give the title compound (31 mg, 47%)
1H NMR (DMSO-d6), δ 12.59 (IH bs), 10 52 (IH. s). 8 93 (IH, s). 8 34 (IH, bs). 7 58
(IH. d, y 1 4 Hz), 7 73 (IH, s), 7 60 (IH, dd, /8 4 and 1 9 Hz), 7 36 (IH, s). 6 75 (IH, s),
6 53 (IH, d J 8.4 Hz), 3 94 (3H, s), 3 42 (3H, s) and 2 41 (3H. s)
APCI-MS m/z 382 1 [MH+]
Example 71
6,7-Dimethoxy-4-(4-methoxycarbonyI-2-methyIanilino)-3-quinolinecarboxamide A mixture of 4-ch]oro-6,7-dimethoxy-3-quinolmecarboxaraide (0 046 g, 0 35 mmol), methyl 4-ammo-2-m6thylbenzoate acid (0 076 g, 0 46 minol) and acetic acid (100 µl) m DMF (0 8 ml) was heated at 100 °C for 9 h After cooling, the mixture was combined with two similar reaction mixtuies (starting from 92 and 46 mg 4-chloro-6,7-dimethoxy-3-qumolinecarboxamide respectively) and diluted with water The mixture was made alkaline with saturated NaHCO3 and the gummy precipitate was collected, washed with water and re-crystallized from methanol to give the title compound (130 mg, 47°o) 1HNMR (DMSO-d6) δ 10 49 (IH. s). 8 94 (IH, i), 8 .35 (JH. bs), 7 88 (IH, d, /MHz), 7.62 (IH, dd,y8 2 and 2 0 Hz), 7 37 (IH, s), 6 53 (IH, dy-= 8 4 Hz), 3 94 (3H, s), 3 80 (3H. s). 3 43 (3H, s) and 2 43 (3H.!,) APCl-MS m/z 395 9[MH+]
Example 72
4-(4-Hydroxyme(:hyl-2-inethylamino)-6,7-dimethoxy-3-quinolinecarbo
xamide
6,7-Dimethoxy-4-(4 methoxycarbonyl-2-methylamino)-3-quinuluiecarboxaraide (0 080 g, 0 20 mmol) was dissolved m tetrahydrofuran (2.i ml, dried over 4 A molecular sieves) Lithium borohydride (0 15 mg, 6 8 mmol) was added The mixture was stirred for 24 h and additional lithium borohydnde (0 050 g, 2 2 mmol) was added The reaction mixture was stirred for additional 25 h and then poured into a cooled mixture of water (20 ml) and acetic acid (0 5 ml) Acetic acid (2 ml) was added and die mixture was evaporated under reduced pressure The residue was suspended in water, filtered and the precipitate was washed with water and re-crystallized from aqueous methanol to give the title compound (32 mg, 43%)
1HNMR (DMSO-d6) δ 11 54 (IH, s), 8 94 (IH, s), 8 46 (III, bsj, 7 86 ^IH, s), 7 69 (IH, bs), 7 31 (IH, d, 7 1 3 Hz), 7 16 (IH, dd, J M and I 4 Hzr), 7 04 (IH, d. / 8 0 Hz), 6 89
(1H, s), 5.20 (1H, t y 5 6 Hz), 4 47 (2H, d, J 5 7 Hz), 3 91 (3H, s), 3 27 (3H, s) and 2 23
(3H. s)
APCI-MS m/z 368 1 [MH+]
Example 73
6,7-Dmethoxy-4-(2-propylanilino)-3-quinulinecarboxamide A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0 062 g, 0 23 mmol) 2-propylanilin (0 038 g. 0 28 mmol), 2-butanole (2 ml), DMF (2 ml) and acetic acid (8 2 µ1) was heated over night at 100C After cooling, the solution was reduced by evaporation The residue was dissolved m water (3 ml) and treated with aqueous ammonia The solid product was filered off washed with water air dried for 0 3 h, washed again with heptane and dried in a vacuum oven at 50C to give a yellow-brown solid, 35 mg (41%) of the title compound APCI-LC/MS m/z 366 1 (MH+) 1H NMR (DMSO-d6) δ 10 95 (IH, s), 8.88 (IH, s). 8 28 (IH, br s), 7 62 (IH, br s), 7 29 (IH, m). 7 24 (IH, s). 7 05 (2H, m), 6 68 (IH, m), 6 63 (IH, s), 3 88 (3H, s). 3 2i (3H, s), 2 67 (2H, t), ] 60. (2H. m), 0 93 (3H, I)
The title compounds of examples 74-86 were prepared by a method analogous to that described m Example 73
Example 74
4-(2-Isopropylanilino)-6,7-Dmethoxy-3-quinolinecarboxamide
1H NMR (DMSO-d6) δ11 07 (IH, s), 8 87 (111, s), 8 28 (IH, or s), 7 58 (111, br s), 7 40
(IH. d). 7 23 (IH, s). 7 13 (lU. t), 7 07 (IH. t). 6 68 (IH, dj, 5 59 (IH, s). 3 88 (3H. s).
3 35 (IH, m), 3 18 (3H, s), 1 27 (6H, d)
APCI-MS m/z 366 1 [MH+]
Example 75
4-[2-(sec-Butyl)amino]-6,7-dimethoxy-3-quinolinecarboxamide
1H NMR (DMSO-d6) δ 11 08 (IH, s), 8 87 (IH, s), 8 28 (IH, br s), 7 59 (IH, br s), 7.34
(IH, d), 7 22 (IH, s), 7 13 (IH, t), 7 07 (IH, t), 6 68 (IH, d), 6 61 (IH, s), 3 86 (3H, s).
3 17 (3H. s), 3 13 (IH, m), 1 65 (2H, m), 1 21 (3H, d). 0 80 (3H, t)
APCI-MS m/z 380 2 [MH-+]
Example 76'
6,7-Dimethoxy-4-[3-(methoxymethyl)-2-methylamino]-3-quinolinecarboxamide
1H NMR (DMSO-d6) 5 10 82 (IH, s), 8 86 (IH, s), 8 2i (HI, br s), 7 58 (IH, br s), 7 22 (IH, s), 7 08 (2H. m), 6 71 (IH, d). 6 64 (IH, s). 4 45 (iH, s), 3 86 (3H, sj, 3 22 (3H, sj, 2 25 (3H, s) APCI-MS m/z 382 1 [MH+]
Example 77
4-[3-(iso-Buloxymethyl)-2-methylamino]-6,7-dimethoxy-3-quinolinecarboxamide 1H NMR (DMSO-d6) δ 10 83 (IH, s), 8 83 (IH. s), 8 23 (IH, br s), 7 58 (IH. br s), 7 22 (IH, s), 7 08 (211, m), 6 72 (IH, d), 6 62 (IH, s), 4 48 (2H, s), 3 86 (311, s), 3 22 (3H, s); 3 19 (2H, d), 2 25 (3H, s),l 80 (IH, m), 0 84 (6H, d) APCI-MS m/z 424.1 [MHH-]
Example 78
4-[i-(cyanomethyl)-2-methylamino-6,7-dimethoxy-3-quinolinecarboxamide
1HNMR (DMSO-d6) δ 10 76 (HI, s), 8 86 (] H, t.), 8 25 (IH, bi t,), 7 oO (IH, br s), 7 24 (IH. s), 7 12 (2H, m) 6 71 (IH, d), 6 61 (IH, s), 4 07 |2H, s), 3 87 (3H. s). 3 22 (3H, s). 2 30 (3H, s; APC'1-LC/MS m/z 377 1 [Mllf]
Example 79
4-{3-[(Ethylamino)methyl]-2-methylamino)-6,7-Dmethoxy-3-quinolinecarboxamide
The title compoundswas piepdred starting Froni tert-butyl 3-amino-2-inethylbenzy](ethy])carbamate, deprotection using TFA gives the title compound 1H NMR (CDCl3) δ 10 68 (IH. b), 8 75 (IH, s), 7 23 (1II, s), 7 13 (IH, d), 7 05 (IH, t), 6 83 (III, d), 6 72 (IH, s), 6 25 (2H, brs), 3 95 (3H, s), ^ 82 (2H. s). 3 31 (3H. s), 2 73 (2n. q), 2 35 (3H, s),0 64 (JH, t) APCI-MS ni/z 395 1 [MH-i]
Example 80
4-{3-[2-(Ethylamino)-2-oxoethyl]-2-methylamino}-6,7-dimethoxy-3-
quinolinecarboxamide
1H NMR (DMSO-d6) δ 10.86 (IH. s), 8 85 (IH, s), 8 23 (IH, br s). 7 94 (IH. m), 7 56 (IH.
br s). 7.21 (IH. s) 7 01 (IH, d), 6 66 (IH, in), 6 62 (IH, s), 3 86 (3H. s). 3 49 (2n. s),
3 21 (3H, s), 3.05 (2H, m), 2 25 (3H. s), 1 00 (3H, t)
APCI-MS m/z 423 3 [MH+]
Example 81
Ethyl 2-(3-{[3-(aminocarbonyl)-6,7-dimethoxy-4-quinoliny]amino}-2-
methylphenyl)acetate
1H NMR (DMS0-d6) δ 10 87 (IH, s). 8 86 (IH, s), 8 26 {IH. br s), 7 56 (IH, brs), 7 22
(IH, s), 7.04 (2H, m) 6 72 (IH. m), 6 16 (IH, s), 4 06 (2H, q). 3 86 (3H. s), 3 76 (2H. s).
3 23 (3H. s). 2 20 (3H, s), 1 15 (3H, t)
APCI-MS m/z 424 1 [MH+]
Example 82
4-[3-(2-Amino-2-oxoethyl)-2-methylamino]-6,7-dimethoxy-3-quinolinecarboxamide 1H NMR (DMS0-d6) δ 10 83 (IH, s), 8 83 (IH. s), 8 24 (IH, hr s), 7 56 (IH, br a), 7 38 (IH, br sj, 7 21 (IH, s) . 7 08 (2H, m), 6 89 (IH, br s), 6 66 (IH, m), 6 62 (IH, s), 3 86 (3H, s), 3 50 (2H, s), 3 22 (3H, s), 2 26 (3H, s) APCI-MS m/z 395 1 [MH+]
Example 83
4-[3-(2-Hydroxyethyl)-2-methyIani]inaJ-6,7-dlmethoxy-3-quinolinecarboxamide 21H NMR (DMSO-d6) δ 10 82 (IH, s), 8 82 (IH, s), 8 23 (IH, br s), 7 56 (IH, br s). 7 22 (IH, s), 7.01 (2H, m), 6 62 (2H, m), 4 66 (111. t), 3 86 (3H. s), 3 55 (2H, q), 3 21 (3H, s). 2 82 (2H, t). 2 27 (3H, s) APCI-MS m/z 382 1 [MH+]
4-(3-{2-[(2-HydioxyethyI)amino]-2-oxoethyl}-2-methylamino)-6,7-dimethoxy-3-quinolinecarboxamide
H NMR (DMSO-de) δ 10 83 (IH, s), 8 82 (IH, s), 8 2i (IH, brs). 7 V5 (IH, m), 7 58 (IH, br s), 7 21(1H, b), 7 03 (2H, m) 6 68 (IH. m), 6 62 (IH, s), 4 65 (IH, t), 3 86 (3H, s), 3 54 (2H, s), 3 39 (2H, m), 3 23 (3H, s), 3 12 (2H, m), 2 26 (3H, si APCr-MS m/z 439 1 [MH+J
Example 85
tert-Buty-3-{[3-(aminocarbony])-6,7-dimethoxy-4-quinoliny]aminio}-2-methylbenzylcarbamate
1H NMR (DMS0-d6) δ 10 83 (IH, s), 8 84 (IH, s), 8 22 (IH, br s). 7 55 (JH, br s),
7 32(IU, in), 7 22 (IH, s) 7 08 (211, m) 6 66 (1II, d), 6 60 (IH, s), 4 15 (2H, d), 3 85 (iH,
s), 3 21 (311, s) 2 25 (3H. s), 1 39 (9H, s)
Al'CI-MSm/z 46 7 2 [MH1-1
Hxamole S6
4-{3-(Aminomethyl)-2-methylamino]-6,7-dimethoxy-3-quinolinecarboxamide Tert-butyl 3- {[3-(aminocarbony)-6,7-dimethoxy-4-quinoliny]amino))-2-methylbenzyl carbamate (0 12 mg, 0 25 mmol) was dissolved in CH2Cl2 (5 ml), cooled on ice and TFA (3 ml) was added Alter 2 h stirringg at room teiiiperaluie the mixture was evaporated to give an oil, which was dissolved in CH2Cl2/aq Na2CO3 solution The aqueous phase was extracted with CH2CI2 (x6) The extracts were washed with brine, dried (Na2SO4), and evaporated The lesidue was purified by chromatography (CH2Cl2/MoOH/NH3) to give the title compound 54 mg, (59%) as a while powder
1HNMR (CDCI3) δ 10 83 (IH, sj,8 82 (IH, s), 8 11 (111, br s), 7 55 (IH, br s). 7 22 (IH, s), 7 16 (IH, d), 7 05 (IH, m), 6 65 (211, m). 3 86 (3H, s), 3 75 (211, s), 3 22 (3H, s), 2 27 l3H, s) APCl-MS m/z 353 1 [MH+]
Enterniediates used as startme metenals 111 examples 87-170
Etyl 7-methoxy- 4-chloro-3-quinolinecarboxamide.
The title compound were prepared essentially as described by Burke el al J Med Chem,
36(1993;425-432
7-Methoxy-4-chloro-3-quinohnecarboxamide
'H NMR (DMS0-d6) δ 8 80 (IH, s), 8 19 (IH, s), 8 15 (IH, br s), 7 90 (IH. br s), 7 50
(IH, d), 7 46 (IH, dd), 3 96 C3H, s)
EllhyM-chloi'o-S-quinolinecarboxamide
The title compound weie prepared essentially a& described by Builce ei al / Med Chem,
36(1993)425-432
4-Chloio-3-quinolinecarboxamide
1H NMR(DMS0-d6) δ 8 8 (IH, s). 8 30 (IH, d), 8 19 (LH, br s), 8 13 (IH, d), 7 96 (IH, brs),7 93(lH,t), 7 83(lH,t)
Ethyl 6.7-dichloro-4-chloro-3-quinolinecarboxamide
The title compound weie prepared essentially as described by Buike etal J Med Chein, 36(1993)425-432
6,7-Dichloru-4-chloro-3-quinolinecarboxamide
'H NMR (DMS0-d6) 5 8 94 (IH, s), 8 47 (2H, d), 8 27 (IH, bi s), 8 06 (IH, br b)
Elyl 6-methoxy- 4-chloro-3-quinolinecarboxamide
The title compound were prepared essentially as described by Burke et al J Med Chem, 36(1993)425-432
6-Methoxy- 4-chloro-3-quinolinecarboxamide
1H NMR (DMS0-d6) δ 8 70 (IH, s), 8 17 (IH, br s), 8 04 (HI, d). 7 92 (IH, br s), 7 56 (IH, dd), 7 52 (IH, d), 3 97 (3H, s)
Exmple 87
4-(4-Fluoro-2-methylanllino)-6-methoxy-3-quinolinecarboxamide
A mixture of 4-flouro-2-methylaniline (0 025 mmol), 6-methoxy-4-chloro-3-
quinolinecarboxamide (0 025 mmol), 50 µl 20% Acetic cid/Ethanol and 250 µl ethanol
was refluxed for four hourb After cooling to room temperdture the solvent was removed m
vacuu
APCI-MS m'z 326 [MH+]
the title compounds of example 88-179 were prepared by a method analogous to that described in Example 87
Example 88
4-(4-Brumo-2-methylamino)-6-methoxy-3-quinulinecarboxamide
APCI-MS m/z 388 [MH+]
Example 89
4-(4-Chloro-2-methylamikno)-6-methoxy-3-quinulinecarboxamide
APCI-MS m/z 342 [MH+]
Example 90
4-(2,4-Dimethylamino)-6-methoxy-3-quinulinecarboxamide
APCl-MS m/z 322[MH+]
Example 91
6-Methoxy-4-(4-methoxy-2-methylamino)-3-quinulinecarboxamide
APCI-MS m/z 338 [MH+]
Example 92
4-(4-Hydroxy-2-methylamino)-6-methoxy-3-quinulinecarboxamide
APCI-MS m/z 324 [MH+]
Example 93
4-(2-Bromoamino)-6-methoxy-3-quinulinecarboxamide
APCI-MS m/z 374 [MH+]
Example 94
4-(2,4-Dimethoxyamno)-6-methoxy-3-quinulinecarboxamide
APCI-MS m/z 354 [MH+]
Example 95
6-Methoxy-4-(2-methoxyamino)-3-quinulinecarboxamide
APCI-MS m/z 324 [MH+]
Example 96
4-(2-Ethoxyamino)-6-methoxy-3-quinulinecarboxamide APCl-MS m/z 338 [MH+]
Example 97
4-(2-Ethylamino)-6-methoxy-3-quinulinecarboxamide
APCI-MS m/z 322 [MH+]
Example 98
6-Methoxy-4-(2-toluidino)-3-quinulinecarboxamide
APCI-MS m/z 308[MH+]
Example 99
6-Methoxy-4-{2-(methylsulfanyl)amino]-3-quinulinecarboxamide
APCI-MS m/z 340[MH+]
Example 100
4-(4-Bromo-2-methylamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 417 [MH+]
Example 101
4-(4-Chloro-2-methylamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 372 [MH+]
Example 102
4-(2,4-Dimethylamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCr-MS m/z 352 [MH+]
Example 103
6,7-Dimethoxy-4-(4-methoxy-2-methylamino)-3-quinulinecarboxamide
APCT-MS m/z 368 [MH+]
Example 104
4-(2-Biomo-4-methylamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 417 [MH+]
Example 103
4-(2-Bromo-4-fluoroamino),7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 421 [MH+]
Example 106
4-(2,4-Dimethoxyamiono)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z. 384 [MH+]
Examnie 107
4-(4-Fluoro-2-methylamino)-7-methoxy-3-quinulinecarboxamide
APCI-MS m/z 326 [MH+]
Example 108
4-(4-Bromo-2-methylamino)-7-methoxy-3-quinulinecarboxamide
APCI-M.S m'z 388 [MH+]
Example 109
4-(4-Chloro-2-melhylanilino)-7-methoxy-3-quinulinecarboxamide
APCI-MS m/z 342 [MH+]
Example 110
4-(2,4-Dimethylanilino)-7-methoxy-3-quinulinecarboxamide
APCI-MS m/z 322 [MH+]
Example 1 ] I
7-Methoxy-4-(4-methoxy-2-methylamino)-3-quinulinecarboxamide
APCI-MS m/z 338 [MH+]
Example 112
4-(4-Hydroxy-2-methylamino)-7-methoxy-3-quinulinecarboxamide
APCl-MS m/z 324 [MH+]
Example 113
4-(2-Bromoamino)-7-methoxy-3-quinulinecarboxamide
APCl-MS m/z 374 [MH+]
Example 114
4-(2-Bromo-4-methylamino}-7-methoxy-3-quinulinecarboxamide
APCI-MS m/z 388 [NH+]
Example 115
4-(2-Bromo-4 -fluoroamino)-7-methoxy-3-quinulinecarboxamide
APCI-MS m/z 390 [MII+]
Example 116
4-(2,4-Dimethoxyamino)-7-methoxy-3-quinulinecarboxamide
APCI-MS m/z 354 [MH+]
Example 117
6,7-Dichloro-4-(4-methoxy-2-methylamino)-3-quinulinecarboxamide
APCI-MS m/z 376 [MH+]
Example 118
6,7-Dichloro-4-(2,4-dimethoxyanilino)-3-quinulinecarboxamide
APCI-MS m/z 392 [MH+]
Example 119
4-(2-Ethylamino)-3-quinulinecarboxamide
APCI-MS m/z 292 [MH+]
Example 120
4-(2-Tomluidino)-3-quinulinecarboxamide
APCr-MS m/z 278 [MH+]
Example 121
4-[2-(Methylsulfanyl)amino]-3-quinulinecarboxamide
Example 122
4'(2-Ethoxyamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 368[MH+1
ExdmpJe 123
4-[2'(Hydroxymethyl)amino]-6,7-dimethoxy-3-quinulinecarboxamide
APCl-MS m/z 354 [MH+]
Example 124
4-(2-Ethylamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCl LC/Ms. m/z 352 [MH+]
APCI-MS m/z 310 [MH+]
Example 125
6,7-Dimethoxy-4-(2-toluidino)-3-quinulinecarboxamide APCI-MS m/z 338 [MH+]
Example 126
6,7-Dimethoxy-4-[2-(methylsulfanyl)amino]-3-quinulinecarboxamide
APCI-MS m/z 370 [MH+]
Example 127
4-(2,4-Dibromoamino)-6,7-dimethoxy-3-quinulinecarboxamide APCI-MS m/z 481 [MH+]
Example 128
7-Methoxy-4-(2-methoxyamino)-3-quinulinecarboxamide
APCI-MS m/z 324 [MH+]
Example 129
4-(2-Ethoxyamnio)-7-methoxy-3-quinulinecarboxamide
APCI-MS m/z 338 IMH+]
Example 130
4-[2-(AminocarbonyI)amanino]-7-methoxy-3-quinulinecarboxamide
APCI-MS m/z 337 [MH+]
Example 131
4-(2-Ethylaniflino)-7-methoxy-3-quinulinecarboxamide
APCI-MS m/z. 322 [MH+]
Example 132 7-Methoxy-4-(2-toluidino)-3-quinulinecarboxamide
APCI-MS m/z 308 [MH+]
Example 133
7-Methoxy-4-[2-(methylsultanyl)amino]-3-quinulinecarboxamide
APCI-MS m/z 340 [MH+]
Example 134
6,7-Dichloro-4-(2-methoxyamino)-3-quinulinecarboxamide
APCI-MS m/z 361 [MH+]
Example 135
6,7-Dichloro-4-(2-ethylamino)-3-quinulinecarboxamide
APCI-MS m/z 360 [MH+]
Example 136
6,7-Dichloro-4-[2-(methylsulfanyl)amino]-3-quinulinecarboxamide
APCr-MS m/z 378 [MH+]
EXAMPLE 137
4-(2,S-Dimethylamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCr-MS m/z 352[MH+]
Example 138
4-(5-Fluoro-2-methylamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 356[MH+]
Example 130
4-(5-Chloro-2-methylamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 372 [MH+]
Example 140
4-(3-FIuoro-2-methylamino)-6,7-dimethoxy-3-quinulinecarboxamide.
APCl-MS m/z 356 [MH+]
Example 141
4-(4-Hydroxy-2,5-dimethylamino)-6,7-dimethoxy-3-quinulinecarboxamide.
APCI-MS m/z 368 [MH+]
Example 142
4-(2-Hydroxy-4-methylamino)-6,7-dimethoxy-3-quinulinecarboxamide.
APCI-MS m/z 354 [MH+]
Example 143
4-Amino-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 324 [MH+]
Example 144
4-(4-Chloro-2-fluoroamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 375 [MH+]
Example 145
4-(2-FIuoroaniImo)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 341 [MH+]
Example 146
4-(2,6-Difluoroanilino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 359 [MH+]
Example 147
4-(3-Bromoamilino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 401,403 [MH+]
Bxample 148
4-(3-Fluoroamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 341 [MH+]
Example 149
6,7-Dimethoxy-4-(4-methoxyamino)-3-quinulinecarboxamide
APCI-MS m/z 337 [MH+]
Example 150
4-(3-Chloroamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 357 [MH+]

Example 151
4-(2-Chloroamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 357[MH+]
Example 152
4-{3-(Acetylamino)amino]-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 380 [MH+]
Example 153
4-(2,5-Difluoroamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 359 [MH+]
Example 154
4-(lH-Indol-5-ylamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 363 |MH+]
Example 155
4-(lH-Indazol-5-ylamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 364 [MH+]
Example 156
4-(lH-Indazol-6-ylamino)-6,7-dimethoxy-3-quinulinecarboxamide

APCI-MS m/z 364 [MH+]
Example 157
4-(2,4-Difluoroamino)-6,7-dimethoxy--3-quinulinecarboxamide
APCI-MS nv'z 359 [MH+]
Exdmnle 158
4-(2-Fluoro-4-methylamino)-6,7-dimethoxy-3-quinulinecarboxamide

APCI-MS m/z 356 [MH+]
Example 159
4-(2,4-Dichloroamino)-6,7-dimethoxy-3-quinulinecarboxamide

APCI-MS m/z 391, 393 [MH+]
Example 160
4-(2,5-Dichloroamino)-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 391, 393 [MH+]
Example 161
4-[2-(2-Hydroxyethyl)amino-6,7-dimethoxy-3-quinulinecarboxamide
APCI-MS m/z 3 68 [MH+]
Example 162
4-(3-Chloro-4-fluoroamino)-6,7-dimelhoxy-3-quinulinecarboxamide

APCI-MS m/z 375 [MH+]
Example 163
6,7-Dimethoxy-4-[3-(methylsulfanyl)amino]-3-quinolinecarboxamide
APCI-MS m/z 370 [MH+]
Example 164
6,7-Dimethoxy-4-(2-methoxy-5-methylamino)-3-quinolinecarboxamide
APCI-MS m/z 368{MH+]
Example 165
4-[4-(Dimethylamino)amino]-6,7-dimethoxy-3-quinolinecarboxamide
APCI-M S m/z 367 [MH+]
Example 166
6,7-D]niethoxy-4-14-(methylsul}anyl)amino]-3-quinolinecarboxamide
APCI-Ms m/z 370 {MH+]
Example 167
4-[4-(2-Hydroxyethyl)amino]-6,7-dimethoxy-3-quinolinecarboxamide
APCl-MS m/z 368 {MH+]
Example l68
4-(3-Hydroxy-4-methoxyamino)-6,7-dimethoxy-3-quinolinecarboxamide
APCI-Ms m/z 370 {MH+]
Example 169
4-(2,3-Dichloroamino)-6,7-dimethoxy-3-quinolinecarboxamide
APCI-Ms m/z391 [MH+]
Example 170 6,7-Dimethoxy-4-(2,3,4-trifluoroamino-3-quinolinecarboxamide
APCI-MS m/z 378 [MH+]
Example 171
6,7-Dimethoxy-4-(3-tolidino)-3-quinolinecarboxamide
APCI-MS m'Z 338 [MH+]
Example 172
4-(2-Hydroxy-4-methylamino)-6,7-dimethoxy-3-quinolinecarboxamide
APCI-MS m/z 354[MH)-]
Example 17 3
4-(2-FIuoro-4-hydroxyamino)-6,7-dimethoxy-3-quinolinecarboxamide:
APCI-MS m/z 358 [MH+]
Example 174
4-[2-(Hydroxymethyl)-4-methylamino]-6,7dimethoxy-3-quinolinecarboxamide
APCI-MS m/z. 368 [MH+]
Example 175
4-(2-Chloro-4-fluoroamino)-6,7-dimethoxy-3-quinolinecarboxamide
APCI-MS n/z 375 [MH+]
Example 176
4-(2-Fluoro-5-methylamino)-6,7-dimethoxy-3-quinolinecarboxamide
APCI-MS m/z 356 [MH+]
Example 177
4-I(2-Cyanopheny)amino-6,7-dimethoxyquinohne-3-carboxmide
APCI-MS m/z 349[MH+]
Example 178
4-[(2,S-Difluorophenyl)amino]-6,7-dimethoxyquinoline-3-carboxamide
APCI-MS m/z 360[MH+]
Example 179
4-(lH-Indo]-5-ylamino)-6,7-dimethoxyquinoline-3-carboxamide
APCI-MS m/z 363[MH+]
Example 180
6,7-Dichloro-4-(2-methylanilino)-3-quinolinecarboxamide.
A mixture of Ethyl-6,7-dichloro-4-(2-methylamino)-3-quinolinecarboxylate (0 050 g, mmol) and NH4Cl was heated m a pressure vessel with NH3-saturated methanol for five days The mixture was evaporated and the residue was recrystallized from EtOH 1H NMR (DMSO-d6) δ 10 9 (IH, s), 9 0 (IH, s), 8 3 (IH. br s), 8 1 (IH. s), 7 7 (IH, br s), 7 6 (IH, s). 7 6 (IH, dd), 7.2 (2H, m), 6 6 (IH, dd). 2 27 (3H, s)
Example 181
4-(2,3-Dihydro-1H-inden-l-ylamino)-6,7-dimethoxy-3-quinoline carboxamide
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0 066 g, 0 25 mmol),
l-aminoindan (0.66 mg, 0 50 mmol), 2-butanole (2 ml), DMF (2 ml) was heated for 48 h at
100°C After cooling, the solution was reduced by evaporation The residue was dissolved
in water (3 ml) and treated with aqueous ammonia The solid product was fitered off
washed with water air dried for 0 5 h, washed again with heptane and dned
The residue was purified by chromatography on silica (CH2Cl2/MeOH) to give 63 mg.
(70%) of the title compound as a white solid
1H NMR (DMSO-d6) δ 8 74 (IH, d), 8 63 (IH, s), 8 05 (IH, br s), 7 55 (1H, s); 7 35 (IH,
br s). 7 30-7 14 (5H, m), 5 46 (IH, q); 3 89 (3H, s), 3 S3 (3H. s). 2 99-2 91 (IH, m); 2 88-
2 76 (IH, m), 2 62-2 52 (IH, m), 1 02-0 91 (IH, m)
APCI-MS m/z 364 1 [MH+]
the title compounds of examples 182-183 were prepared by a method analogous to that described m Example 181
Example 182
6,7-Dimethoxy-4-{[2-(trifluoromethyl)benzyl]amino}-3-quinoline carboxamide 1HNMR(DMS0-d6) δ 8 91 (IH, t), 8 59 (IH, s), 7 98 (IH, brs), 7 75 (2H, m), 7.68 (IH, t). 7 51 (IH, t), 7 34 (IH, br s), 7 25 (IH, s), 7 21 (IH, s), 4 91 (2H. d), 3.88 (3H. s), 3 51 (3H, s) APCI-MS m/z 406 1 [MH+]
Example 183
6,7-Dimethoxy-4-[(l-phenylethyl)amino]-3-quinolinecarboxamide
1H NMR (DMSO-d6) δ 9 40 (IH, d), 8 66 (IH. s), 8 06 (JH, br s), 7 43-7 35 (2H, m), 7 30
(2H, 0,7 18-7 22 (2H, m), 7 14 (IH, s), 5 18 (IH, m), 3 83 (3H, s); 3 45 (3H. s), 1 52 (3H,
d)
APCI-MS m/z 352 1 [MH+]
Example 184
4-(3-Hydroxymethyl-2-methylamino)-3-quinolinecarboxamide
a) Diethyl 2-[1,3-beuzodiuxoI-5-yIanuno)inethyleneJmaIoiidte
Diethyl 2-(ethoxymethyIene)malonate (4 1 ml, 20 3 mmolj 3,4-methyleiiedioxyamlme
(2 77 g, 20 2 mmol) was stirred under mtrogen at 120 °C for 2 5 h The reaction mixture
was cooled and ethanol was added The precipitate was collected by filtration and re-
ciystallized from ethanol to give the title compound (3 52 g, 56%)
1H NMR (DMS0-d6) δ 10 67 (IH, d. 713 9 llz), 8 28 (IH, d, 713 9 Hz), 7 12 (111, d, J
2 2 Hz), 6 91 (IH, d, J 8.3 HzJ, 6 81 (IH, dd. 7 8 4 and 2 3 liz), 6 04 (2n, s), 4 19 (2H, q, J
7 1 HzJ, 4 10 (2H, q, 7 7 1 Hz), 1 25 (3H, t, 77 1 Hz), and ] 23 (3H, t,J7 2 llz)
b) Ethyl 4-chloro-6,7-methylenedioxy-3-quinolinecarboxamide
Diethyl 2-[l,3-benzodioxal-5-ylamino)methy]ene]malonate (3 25 g, 11 6 inmol) was
dissolved in POCI3 (60 ml) and heated at reflux for 4 5 b, cooled and co-evaporated twice
with toluene The residue was suspended m ice-culd saturated aqueous NaHC03 and the
precipitate was collected by filtration, nnsed with water and dried to give the title
compound (3 01 g, 95%)
1H NMR (DMS0-d6) δ 8 92 (IH, s), 7 64 (IH, s), 7 49 (IH, s), 6 33 (2H, s), 4 40 (2H, q,
77 1 Hz) and 1 36 (3H, t, 77 1 Hz)
ATCI-MS m/z 279 9 [MH+]
c) 4-Chloro-6,7-methylenedioxy-3-quinolinecarboxylic acid
Ethyl 4-chloro-6,7-methylenedioxy-3-quinolinecarboxylate (1 54 g, 5 5 mmol) was suspended in a mixture of ethanol (25 ml), THF (5 ml) and aqueous 2 M NaOH (25 ml) and stirred at ambient temperature for 2 h The reaction mixture was neutralized with 1 M aqueous HCl and the organic solvents were evaporated under reduced pressure After acidification to pH 2-3 with 1 M HCl the resultmg precipitate was isolated by centrifugation The precipitate was re-suspended in water and centrifuged again The procedure was repeated twice to give, after drying, the title compound (1.25 g, 90%) 1H NMR (DMSO-d6) δ 13 71 (IH. bs), 8 93 (IH, s). ' 63 (IH, s), 7 47 (IH, s) and 6 32 (211, s)
d) 3-Chloro-6,7-methylenedioxy-3-quinohnecarboxamide
4-Chloro-6,7-methylenedioxy-3-quinolineoarboxyliL acid (0.68 g, 2 / mmol) was suspended in thionyl chloride (30 ml) and the mixtuie was heated to rellux for 1 h and then co-evaporated with toluene The residue was suspended in ice-oold acetone (25 ml) and treated with ice-cold saturated aqueous ammonia (28%, 2 ml) in portions at 0°C The reaction mixture was stirred at 0 °C fur 2 mm and then filtered The solid material was washed with water and dried to give the title compound (501 mg, 74%) 1H NMR (DMSO-d6) δ 8 63 (IH, s,). 8 10 (IH, bs), 7 84 (IH, s). 7 56 (IH, s), 7 46 (IH s; and 6 30 (2H, s)
e) 4-(3-Hydroxymethyl-2-melhyamino)-3-quinolinecurboxamide
A mixture of 3-Chloro-6,7-methylenedioxy-3-qurolinmecoxamide (106 mg, 0 42 rnmol),
3-ammo-2-metliylbenzyalcohol (72 mg, 0.52 mmol) and acetro acid (100 µL) in DMF (2
ml) was heated at 100 °C foi 6 h After cooling, the mixture was diluted with water (20 ml)
and washed twice with ethyl acetate The aqueous phase was made alkaline with 1 M
NaOH and the resulting precipitate was collected by filtration, washed with water and dned
to give the title compound (113 mg, 75%)
1H NMR(DMSO-d6) δ 10 47 (IH, s), 8 86 (IH, s), 8 30 (IH, s). 7 64 (IH, s), 7 26 (IH,
s), 7 13 (IH. d, J7 3 Hz), 7 00 (IH, t, 7 7 7 Hz), 6 66 (111, s), 6 49 (IH, d, j7 8 Hz), 6 11
(2H, s), 5 14 (IH. bs). 4 56 (2H. s) and 2 28 (3H, s)
APCI-MS m/z 352 1 [MH+]
Example 185
9-(3-Hydroxymethyl-2-methylamino)-2,3-dihydro[l,4]dioxinol2,3g]quinolme-8-carboxamide
a)Ethyl9-chloro-2,3-dihydro[l,4]dloxino[2,3jr]quinoline-8-carboxylate
Diethyl 2-(ethoxymethylene)malonate (4 1 ml, 20 3 mmol) and 2,3-dihydro-l,4-benzodioxin-6-amine (2.4S ml, 20 2 ramol)) was stirred under nitrogen at I20°C for 4 h and the reaction mixture was then evaporated under reduced pressure The crude diethyl 2-[2,3-dihydro-l,4-ben2odioxm-6-ylamino)methylene]malonate was dissolved m POCI3 and healed at reflux for 5 h and the mixtuie was then co-evaporated with toluene The residue was dissolved in methylene chloride and washed with saturated aqueous NaHCO3 and water, dned (Na2SO4), filtered and evaporated The residue was crystallized from methanol-water to give 3 5 g of crude produci Re-crystallization from rnethanol-water and finally from methanol gave the title compound (1 14 g, 19%;
1H NMR DMSO-d6) δ 8 93 (IH, s), 7 65 (IH, s), 7 51 (IH, s), 4 49-4 42 (4H. m), 4 40 (2H, q, y 7 1 Hz) and 136 (3H, t. J77 Hz) APCI-MS m/z 293 9 [MH+]
b)9-Chloro-2,3-dihydro[l,4]dioxino[l,3f]quinoIine-ii-carboxylic acid
Ethyl 9-chloro-2,3-dihydro[l,4]dioxino[2,3g]quinoline-8-carboxylate (1 1 g, 3 7 mmol) was dissolved m a mixture of ethanol (20 ml) and THF (5 ml) Aqueous NaOH (2M, 20 ml) was added After stirring at ambient temperature for 1 45 min the reaction mixture was acidified with 1 M HCl The organic solvents were evaporated under reduced pressure and the crude product was isolated by centnfugation After decantation, the precipitate was re-suspended in water centrifuged again The procedure was repeated twice and the precipitate was finally dned to give the title compound (0 65 g, 65%) 1H NMR (DMSO-d6) δ 13 78 (IH, bs). 8 94 (IH, s), 7 66 (IH, s), 7 51 (IH, s) and 4 45 (4H,s)
c) 9-Chloro-2,3-dihydro[1,4]dioxino[1,3g]quinoline-8-carboxamide
9-Chloro-2,3-dibydro[l,4]dioxino[1,3g]quinohne-8-carboxylic acid (0 61 g) in thronyl chloride (30 ml) was heated at reflux for 3 h and the reaction mixture was then co-evaporated with toluene The residue was suspended in ice-cold acetone (25 ml) and treated with ice-cold saturated aqueous ammonia (28%, 1 5 ml) m portions at 0°C The reaclion mixture was stirred at 0 °C for 2 mm and then filteied The solid material was washed with water and dried to give slightly impure title compound (435 mg, 71 %) From
the aqueous filtrate was precipitated additional title compuund (91 mg) which was
sufficiently pure to be used without further punfication
1HNMR (DMSO-d6). δ8 64 (IH, s), 8 10 (IH, bsj, 7 85 (,1H, bs), 7 58 (IH,s), 7 50 (IH,
s)and 440(4H,s)
APCI-MS m/z 265 0 [MH+]
d)9-(3-Hydroxyraethyl-2-inethyIanilinu)-2,3-dihydro(l,4]dioxinoI2,3]quinoline-8-carbuxainidc
A mixture of 9-chloro-2,3-dihydro[l,4]dioxino[l,3g]quinoIine 8-carboxainide (0 090 g, 0 34 mniolj, 3-amino-2-methylbenzylalcohol (0 058 g, 0 45 mmol) and dceoc acid (80µl) m DMF (1 6 ml) was heated at 100'C for 3 h Aftei cooling, the mixture was diluted with water and made alkaline with 1 M NaOH Methanol was added and the mixture was heated to partially dissolve the gummy precipitate After coohng the precipitate was collected by filtration, washed with water and dried to give the title compound (98 mg, 75%) 1H NMR (DMSO-d6) δ 10 78 (IH, s), 8 85 (IH, s) 8 27 (IH, bi), 761 (IH, bs), 7 26 (IH, s), 7 17 (IH, d, J 7 4Hz), 7 03 (IH, t, J 7 6 Hz), 6 79 (IH, s), 6 59 (IH, d 17 9 Hz). 5 17 (1H, t, J 5 2 Hz), 4 57 (2H, d J 5 2 Hz), 4 31 (2H, s), 4 21 (21:1, s) and 2 27 (3H, s) APCI-MSm/z 366 1 [MH+]
The title compounds of examples 186-195 wcic piopaied by a inetLod analoguus to that described in Example 3
Example 186
4-[(2-ethylphenyl)amino]-7-methoxy-6-[2-(propylamino)ethoxy]qumoline-3-carbuxamide
APCI-MS m/z 423 [MH+ ]
Example 187
6-[2-(ethylmino)efhoxyj-4-[(2-ethylphenyl)animoJ-7 methoxyquinulme-3-carboxamide
-APCI-MS m/z 409 [MH+]
Example 188
6-[2-(isopropyIamino)ethoxy]-7-methox.y-4-[(3-methoxy-2-methylphenyl)amino]qumohne-3-carboximide
APCI-MS m/z 439 [MH+]
Example 189
6-[2-(dimethylamino)ethoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-methoxyquinoline-3-carboxainide bis(trifuoroacetate)
APCI-MS m/z. 667 [MH+]
Example 190
5-[3-(diethyIamino)propoxy]-4-{[3-(hydroxymethyl)-2-methylpenyl]amino}-7-methoxyqumoline-3-carboxamide
APCr-MS m/z 467 [MH+]
Example 191
4-{[2-ethyl-3-(hydruxymethyI)phenyl]amino}-7-methoxy-6-[2-(methylainino)ethoxy]qumohne-3-carboxamide
APCI-MS m/z 425 [MH+J
Example 192
4-[(2-ethylphenyI)aininoJ-7-methoxy-6-{3-(pyridin-4-ylumino)propoxy]quinoline-3-carbuxamldebis(trifluoroacetale)
APCI-MS m/z 700 [MH+]
Example 193
4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-[(2-aniino-2-oxoetliyl)aminopropoxy]-quinoline-3-carboxamide
APCI-MS m/z 680 [MH+]
Example 194
4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-(lH-pyrazol-3-ylamino)propoxy]quinoline-3-carboxamide trifluoroncetate
APCI-MS m/z 575[MHl-J
Example 195
4-[(2-ethylphenyI)amino]-7-methoxy-6-[3-(pyridin-2-ylamino)propoxy]quinoline-3-carboxaniide bis(trifluuroacetate)
APCI-MS m/z 700 [MH+]
The title compound of Example 196 were prepared by a method analogous to that described in Example 12
Example 196
Ethyl4-[P-(aminocarbonyl)-4-{[2-ethyl-3-(hydroxymethyl)phenyl]anino}-6-methoxyqumolin-7-yl)oxy]bulanoate triifluoroatetate APCI-MS m/z 591 [MH+]
The title compounds of examples 197-218 were prepared by a method analogous to that described in Example 23
Example 1 97
7-(3-(diethylamino)propoxy]-6-methoxy-4-[(2-methoxyphenyl)amino]quinoline-3-carboxamide
APCf-MS in/z 453 [MH+]
Example 198
7-(3-(ethylamino)propoxy]-6-methoxy-4-{[2-(trifluoromethyl)phenyl]amino)quinuline-3-carboxamide:
VPCI-MS m/z 463 [MH+]
Example 199
7-[3-(ethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide
APCI-MS m/z 423 [MH+]
Example 200
4-[(2-ethylphenyl)amino]-7-[3-(isopropylamino)propoxy]-6-methoxyquinoline-3-carboxamide
APCI-MS m/z 437 [MH+]
Evample 201
7-13-(ethylamino)propoxyl-4-{[2-etliyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquiniline-3-carboxamide
APCI-MS m/z 453 [MH+]
Example 202
4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(propylamino)propoxy]quinoline-3-carboxnide
APCI-MS m/z 467[MH+]
Example 203
7-[3-(dimethylamino)propoxy]-4-[(2-ethylphenyi)amino]-6-methoxyquinoline-3-carboxamide bis(trifluoroacetate)
APCI-MS m/z 651 [MH+]
Example 204
4-|(2-ethylphenyl)amino]-6-methoxy-7-(3-pyrrolidin-l-ylpropoxy)quinoline-3-carboxaiiiide bis(trifluorocetate)
APCI-MS m/z 677 [MH+]
Example 205
7-[3-(diethylamino)propoxy]-4-[(2-etliylphenyI)amino]-6-methoxyquinoline-3-carboxamide bis(trifluoroacetate)
APCI-MS m/z 679[MH+]
Example 206
4-[(2-ethylphenylamino]-6-methoxy-7-(3-prperidin-1-ylpropoxy)quinoline-3-carboxamide bis(trifluoroacetate)
APCI-MS m/z 691 [MH+]
Example 207
7-[3-(dimethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-niethoxyquinoline-3-carboxamide bis(trifluoroacetate) APCl-MS m/z 681 [MH+]
Example 208
7-[3-(diethylamino)propoxyl-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-inethoxyguinoline-3-carboxamide bis(trif1uoroacetate)
APCI-MS m/z 709[ MH+]
Example 209
7-{3-I(2-ethoxyethyl)amino]propoxy}-4-[(2-cthylphenyl)amino]-6-methoxyquinoline-3-carboxamide
APCl-MS m/z 467 [MH+]
Example 210
4-[(2-ethylphenyl)amino]-6-methoxy-7-(3-prperation-1-ylpropoxy)quinoline-3-carboxamide
APCl-MS m/z 463 [MH+]
Example 211
4-[(2-ethylphenyl)amino]-6-methoxy-7-(3-thromorpholin-4-ylpropoxy)quinoliine-3-carboxamide
APCI-MS m/z 481 [MH+]
Example 212
4-{[3-(hydroxymethyl)-2-methylphenyl]amino}-6-methoxy-7-(3-pyrrolidin-l-yIpropoxy)quinoline-3-carboxainide
APCl-MS m/z 465 [MH+]
Example 213
7-[3-(l,l-dioxidothioinorpholin-4-yJ)propoxy]-4-[(2-ethylphenyl)atnino]-6-inethoxyquinoline-3-carboxaniide
APCl-MS m/z 513[MH+J
Example 214
4-{[2-etliy]-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-(3-pyrrolidin-l-ylpropoxy)qumoline-3-carboxatnide
APCI-MS m/z 479 [MH+]
Example 2 n
4-{[2-ethyl-3-(hydraxymethyl)phenyl]aminn}-6-methoxy-7-(3-pipendin-l-y]propox}')qumoliiie-3-carbuxamide
APCI-MS m/z 493 [MH+]
Example 216
4-{[3-(liydroxymethiyl)-2-metliylphenyl]amino}-7-[3-(3-hydroxyprperidin-l-yI)propoxy]-6-methoxyquinoline-3-carboxmide
APCl-MS m/z 495[MH+]
Example 2l7
4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino|-6-methoxy-7-[3-(lH-l,2,4-triazol-l-yI}propoxy]quinoline-3-carboxamide bis(trifluoroacelate)
APCl-MS m/z 705 [MH+]
Example 218 7-(3-azepan-l-ylpropoiy)-4-[(2-ethylphenyl)araino]-6-methoxyquinoline-3-carboxamide
APCI-MS m/z 477[MH+]
The title compounds of examples 219-222 were prepared by a method analogous to that described m Example 87
Example 219
6,7-dimelhoxy-4-{[2-(methylthio)phenyllamino}quinuline-3-carboxamide tnfluoroacetate
APCI-MS m/z 484[MH+]
Example 220
6,7-dimethoxy-4-[(4-methaxy-2-niethylphenyl)aniini)jquuiuline-3-camide trifluorualelate
APCI-MS m/z 482|MH+]
Exdmple 221
4-{[2-bromu-3-(iiydruxymetiiyI)pheiiyIJaminoj-(),7-dimeethoxyqineline-3-carboxamide
APCI-MS m/z 433 [MH+]
Hxaiiinle 222
4-{[2-ethyJ-3-(hydroxyinethyI)phenyl]amino}-6,7-dimemoxyquinolure-3-carboxamide APCI MS m/z J82[MH+1
Syntheses of anilines used above
Methyl 2-methyI-3-nitrobenzyl ether
To d solution of sodiun (0 lU g, 4 3 mmoJ) in methanol (40 ml) was added 2-methyl-3-iiitrobenzylchlonde (0 50 g, 2 7 nunol) and caialytic amoimtb of Lil undca- nitogen After the ledction occurred at 40°C over night, the solvent evapurred and the residue was puiified
by chromatogrphy (heptane/EtOAc) to give the title compound 450 mg, (92%) as a yellow
oil
1H NMR (CDCl3) δ 7 70 (IH, d), 7 58 (IH. d), 7 29 (IH, t), 4.49 (2U. s), 3 43 (3H, s),
2 42 (3H, s)
Isobutyl 2-methyl-3-nitrobenzyI ether
The same procedure ds in methyl 2-methyl-3-nitrobenzyl ether was used, to give the title compound 486 mg, (81%) as a yellow oil
1H NMR (CDCl3) δ 7 71 (IH, d), 7 58 (IH, d), 7 29 UH. t), 4 52 (2H, s), 3 27 (2H, d), 2 42 (3H, s), 1 91 (IH. m), 0 93 (6H, d)
3-(Methoxymethyl)-2-methylanihne
A mixture of methyl 2-methyl-3-nitroben2yl ether (0 19 g, 1 05 nimolj, and 5% Pd/C (70 mg) in EtOAc/EtOH 1 1 (14 ml) was hydiogenated ai 1 atm ovei night The mixture was filtered llirough Celite, and the filtrate was concentrated to give the title compound 125 mg (78%) as a yellow oii
1H NMR (CDCI3) 5 6 99 (IH, t), 6 75 (IH d), 6 66 (llf, d), 4 42 (2H, s), 3 60 (2H, br s), 3 37 (3H, i), 2 12 (3H. s)
3-([sobutoxymethyI)-2-metliy]aniJine
The title compound was prepared by the same procedure as m 3-(mBthoxyniethyl)-2-
mechylaniline
1H NMR (CDCl3) δ 6 99 (IH, t), 6 76 (IH, d), t) 65 (IH. d). 4 46 (21 f, s), 3 60 (2H, br s),
3 21 (2H, d), 2 13 (3H, s), 1 89 (IH, m), 0.9J (oH, d)
2-(3-Aminu-2-methylpheuyl)aLetoiiitrile
2-(2-MethyI-3-nitrophenyl)acetonitriIe (Askam, V etal S L'hera Soc C (1969)1935-1936,) was hydrogenated over 5% palladium-charcoal 50 mg n EtOAc'EtOli I 1 (14 ml) for three hours The mixture was filtered thiough celite, and the filtrate was concentrated to give the title compound 77 mg (77%) as a whits powder
1II NMR (CDCl3) δ 7 03 (IH, t), 6 78 (IH, d), 6 68 (IH, d), 3 66 (2H. br t,), 3 63 (2H, s). 2 22 (3H, s)
N-(2-methyl-3-nitroben/yl)-l-ethanamine
A mixture of 2-methyl-3-nitrobenzylchloride (0 50 g, 2 7 mmol) and ethylamine (2 76 g, 61,2 mmol) m THF (10 m)/MeOH (5 mi) was stirred at amluend tempeiature for 48 h The solvent was reduced and the recidue was dissolved in EtOAc/aq K2CO3solution The aqueous phase was extracted with ElOAc (x2) The combined 01 game layers were washed
with bnne, dried (Na2SO+), and concentrated to give the title compound 0 46 g (86%) as a yellow oil
1H NMR (CDCI3) 5 7 65 (IH, dj, 7 55 (IH, d), 711 (IH, d), 3 83 (2H, s), 2 72 (2H, q). 2 45 (3H. s), 1 15 (3H, t)
3-[(Ethylamino)methylJ-2-methylaniline
N-(2-methyl-3-nitrobenzyl)-l-ethanamine (0.46 g, 2 3 mmol) was hydrogenaled over 5% palladium-charooa] 80 mg in EtOAc/ErOH 1 1 (14 ml) foi four hours The mixture was filtered through celite, and the filtrate was concentrated to give the title compound 0 373 g (97%) as d pale yellow oil
1H NMR (CDCI3) δ 6 98 (IH, t), 6 74 (1H, d). 6 62 (IH, d), 3 74 (211, s), 3 bO (2H, br s), 2 71(2H,q).2I4(3H,s), 1 13 (3H. t)
tert-Butyl 3-amino-2-methylbenzyl(ethyI)carbainatc
To a solution of 3-[(ethyIdmino)methylJ-2-methylaniIiiie (0.32 g, 1 95 mmol) in TPIF (20
ml), was added di-tert-butyl dicarbonate 0 43 g (1 97 imnol) After 16 h stirring at ambient
temperatuie, the solvent evaporated, and the residue was purified by chromatography to
give the title compound 0 51 g (99%) as a colourless oil
1H NMR (CDCI3) δ 6 97 (IH, s), 6 61 (2H, m), 4 42 (2H, br s), 3 60 (2H, br s), 3 12 (2H,
br d), 2 OS (3H, s). ] 45 (9H, br s), 0 98 (3H, br s)
tert-Butyl 2-aminobenzylcarbamate
To ice cooled solution of 2-amino-benzylamine (1 2 g, 10 mmol) m THF (70 ml) was added di-tert-bulyl dicarbonate (2 15 g, 9 9 mmol) After 18 h stirnng at ambient lempeiature, the solvent was reduced and the precipitate was collected by filtration, washed with cold ether (x2), heptane (x2) and dried, to give the ntle compound 1 9 g (85%) as a pale yellow powder
1H NMR(CDCl3) δ 7 09 (IH, m), 7 02 (IH, m), 6 66 (IH, m), 4 76 (IH, br 3), 4 25 (2H, d), 4 21(211, brs), 1 43 (9H, s)
2-(3-Amino-2-methyIphenyI)-N-ethylacet amide
A mixture of 2-(3-amino-2-methylphenyl)acetic acid (0 32 g, 1 78 mmol) and thionyl
chloride (2 ml) was refluxed for 1 5 hour /fter cooling the excess thionyl chloride was
removed by evaporation Last traces of thionyl chlonde were removed by azeotropmg with
toluene
The residue dissolved m dry ttO Ac (2 ml) and cooled in an ice-bath lithylamme (2 ml)
was added and the leaction occuned over night at ambient :emperature The organic layer
was washed with water, brue, dried over Na2SO4 and evporated to give an white powder,
which was hydrogenated on 5% palladium-chdrcoal (70 mg) m EtOAc/EtOH 1 1 25 ml for 3 hours The mixture was filtered through celite, and the filtrate was concentrated to give an oil which was further punfied by chromatography on silica, (CH2Cl2/MeOH), to give 0 266 g (78%) of the title compound as a white solid
1H NMR (CDCl3) δ 6 99 (IH, t), 6 65 (IH, d). 6 6J (JH, d), 5 32 (1H, bi s), 3 66 (2H, br s). 3 55 (2H. s), 3 20 (2H, m), 2 41 (3H, s), 1 05 (3H, i)
2-(3-amino-2-methylphenyl)-A^-(2-IiydioxyethyI)iicetaniide
A mixture of 2-(3-amino-2-methylphenyl)acetic acid (0 33 g, 1 84 mmol) and thionyl
chloride (2 ml) was refluxed for 1 5 hour After cooling the excess thionyl chloride was
removed by evaporation Last traces of thionyl chlondc were removed by azeotropmg with
toluene
The residue dissolved in dry EtOAc (2 ml) and cooled m an ice-bath 2-Aminoethanol (2
ml) was added and the reaction occurred overnight at ambient teiupcratuie The organic
layer was diluted with ElOAc (15 ml), washed with water, brine, dried over Na2SO4 and
evaporated to give an white powder, which was hydiogenated on 5% palladium-cliarcoal
(70 mg) in ethanol (20 ml) over night The mixluie was filtered through celite, and the
filtrate was concentrated to give 0 28 g (73%) of the title compound as a white solid
1H NMR (DMSO-d6) 6 7 69 (IH, m), 6 77 (IM, t), 6 49 (HI, d), 6 39 (IH, d). 4 70 (2H, br
s), 4 62 (1II, t), 3 36 (2H, q), 3 34 (3H. s), 3 09 (2H, q), 1 93 (3H, s)
APCI-MS m/z 209 2 [MH+]
3-(Aminomethyl)-2-methylamline
A mixture of 2-methyI-3-nitrobenzy]chloride (0 70 g, 3 77 mmol), sodium azid (1 g, 15 4 mmol), ethanol (10 ml) and water (2ml) was. heated at 45'C overnight The mixture was filteied, the filtiate was concentrated, and the residue was punfied by chromatography ou silica (heptane/EtOAc) to give the compound 2-methy)-3-niticbenzylazide 0 35 g, which was hydrogenated over 5% palladium-charcoal 80 mg in EtOAc/EtOH 1 1 (14ml), over night The mixture was filtered through Celite, and the filtrated was. concentrated to give 0 23 g (45%) ot the title compound as a white solid
1H NMR (DMSO-d6) 6 6 79 (III, t), 6 52 (2H. t), 4 67 (211, bi s), 3 59 (2H, s), I tert-Butyl 3-amino-2-methylbenzylcarbamate
To a solution of 3-[(ethylamino)methyl]-2-methylaniline (0 21 g, 1 54 mmol) in THF (20 nil), was added di-tert-butyl dicarbonate (0 35 g,l 97 mmol) After 18 h sturing at ambiend temperatuie, the solvent evaporated, and the residue was punfied by chromatography on silica (CH2Cl2/MeOH) to give 0 51 g (99%) of the title compound as a colourless oil
1HNMR(CDCl3) δ 6 99 (IH. t). 6 69 (IH, d). 6 64 (IH, d), 4 63 (IH, brs); 4 29 (2H, d), 3 63 (2H. br s), 2 10 (311, i). 1-45 (9H, s)
3-(2-Nitiuphenyl)propanoic acid
The title compound was prepared by a modification of the piocedure reported by Grob et al Helv Chim Acta 206(1961)1736-1747
Sodium hydnde (60 % m paraffin oil, 1 0g, 23 mmol) was added to a solution of diethyl malonate (3 2 g, 20 mmol) m DMF (20 ml) and the mixture was stirred for 3 nun 1-BromomethyI-2-mtiobenzene (4 3 g, 20 mmol) was then added in portions dunng 5 mm The reaction mixture was stirred for 3 h, diluted with water, and extracted twice with ethyl acetate The combined organic phases was washed with water and evaporated The residue was suspended in acetic acid (40 ml) and 7 5 M HCl (10 ml) was added The mixture was refluxed for 19 h, cooled and partitioned between diethyl ether and satuiated aqueous NaHCO3 The organic phase was washed with saturated aqueous NaHCOs and then acidified with 2M HCl The precipitate was collected by filtration and dried to give the title compound (2 22 g, 77%)
1H NMR (CDCI3) δ 7 97 (IH, dd, 78 1 and 1,3 Hz), 7 57 I'lH, dt, 77 5 and 1 3 Hz), 7 47-7 37 (2H, m), 3 24 (2H, t, 77 6 Hz), and 2 81 (2H, t, ; 7 6 Hz)
4-Nitro-l-indanone
The title compound was piepared essentially as described by Giob et al Helv Chim Acta 206(1961)1736-1747
3-(2-Nitrophenyl)prupanoio acid (2 17 g, 11 1 mmol) m tltionyl ohlonde (30 ml) was heated at reflux temperatuie for 1 5 h and the reactton mixture was then evaporated The residue was dissolved m carbon disulfide (IS ml, distilled ovei AICI3) and AlCI) (3 2 g, 24 mmul) was added with stunng The mixture was heated at reflux lempeiature for 4 h and the solvent was then evaporated usmg a stream uf nitrogen at ambient temperature To the residue was added with stiring a mixtuie of concentrated H2SO4 (5 3 ml) and ice (33 g) followed by toluene (25 ml) The mixture was stirred until all solid material was dissolved and the organic, phase was then separated The water phase was extracted twice with diethyl ether and the combmed organic phases were washed subsequently with saturated NaHCO3, water and brine and finally dried over MgS04 filtered and evaporated The residue was chromatographed on a column of silica (2x18 em) using ethyl acelate-heptane (1 3) as eluent to give the title compound (0 8 g, 40%)
1H NMR (CDCI3) δ 8 49 (IH, dd, 78 0 and 1 1 Hz), 8 10 (IH, d, Jl 5 Hz, further coupled), 7 63 (IH, t, y 7 8 Hz, further coupled), 3 67 (2H, ni) and 2 82 (2H, ni)
4-Amino-l-indanone
4-Nitro-l-indanone (0 84 g, 4 75 mmol was suspended in aqueous hydrochloric acid (9 M,
40 ml) and stannous chloride (3 g, 15 8 mmol) was added The mixture was stirred at
ambient temperature After 2 h a clear solution was obtained The stirring was continued
for 23 h after which time a yellow precipitate had formed The reaction mixture was diluted
with water and washed trice with methylene chlonde The aqueous phase was made
alkalme with 2 M aqueous NaOH and extracted four times with methylene chlonde. The
combined organic phases was washed with water, dned (Na2SO4), filtered, evaporated and
finally dned to give the title compound (630 mg, 90 %)
1H NMR (CDCl3) δ 7 28-7 18 (2H, m), 6 93 (IH, d, ,77 0 Hz), 2 92 (2H, t, J5 6 Hz,
iiirtber coupled) and 2 71 (2H, t,J5 5 Hz, further coupled^.
2-Bromu-3-aminobenzyl alcohol
The compound is reported in (Cladmgboel, David E et al J Chem Soc Chem Commun , EN, 21, 1990,1543-1544)
Methyl 3-nitio-2-vinylbenzoate
The compound is reported m (Soderberg, Bjom C et al J Org Chem 1997, 62, 5838-5845).
Methyl 3-amino-2-ethylbenzate
A mixture of methyl 3-intro-2-vinylbenzoale (1 1 g, 5 31 minal), and 5% Pd'C (100 mg) ml EtOAc/EtOII 1 1 (50 ml) was hydrogenated al J atm over night The mixture was filtered through Celite, and the filtrate was concentrated to give the title compound 0 93 g (97%) as a colouiless oil
1H NMR (CDCI3) d 7.20 (IH, q), 1 05 (IH, t), 6 82 (IM, q;, J 88 (3H, s). J 75 (2H, brs),2 78(2II.q), 124(3H,t)
(3-Aniinu-2-ethyIphenyI)methanol
To a solution of methyl 3-amino-2-ethylbenzoate (0 83 g, 4 03 mmol), m THF (40 ml) was added Litluum aluminium hydride (0 9 g, 23 7 mmol) The mixture was heated at 50 C for 5 h, cooled to 0 C and hydrolysed cautiously with water. The slurry was extracted with EtOAc, (x 5) The extracts were washed with drive, dried Na2SO4, and evaporated The
residue was punfied by chromatography (CH2Cl2/MtOH) to give the utle compound 0 63 g (89%) as a white powder
1H NMR (CDCI3) δ 7 05 (IH, t), 6 82 (IH, d), b 70 (111, d), 4 68 (211, d), 3 71 C2H. bri), 2 68 (2H. q), 1 47 {Iti. t), 1 23 (3H. t)
Pharmacological Data
JAK3 HTRF assay
The JAK3 kinase assay utilizes a fusion prolem (Jak3 kinass domain fused to Glutathione S-transferase, GST) coexpressed m E Coli with GroEL/S, and purified by affinity chromatography on Glutathione Sepharose The enzyme is diluted in 10 mM Tris-HCl, 150 mM NaCl, 5% mannitol, 2 mM 2-mercaptoetanol and 30% glycerol The substrate in the kinase reaction is a biotinylated peptide of the autophosphoiylation site oi JAK3 (biotiii-LPDKDYYVVREPG)used at 2 µM Assay conditions are as follows JAK3, cnmpuund and substrate are mcubated in 25 mM Tnzma base, 5 ,M MgCl2, 5 mM MnC12, 0 05% TntonX-100 and 2 µM ATP for 45 mm at RT Reaction volume is 20 µM Slopsolution is added for a final concentration of 100 µM iZDTA Finally 0 065 mg/ml PT66-K: and 10 42 µM SA-XL665 are added in 50 mM Hepes, 0 5 M KF and 0 1% BSA The plate is lead in a Discovery instrument atter 60 mm incubation
The compounds of the examples have an IC'50 less than 25 µM






WE CLAIM:
1. 4-anilinoquinoline-3-carboxamides of formula (IA):
(Formula Removed) in which
Ar is phenyl substituted by ethyl, propyl, hydroxymethyl or CO2H or
disubstituted by methyl and hydroxymethyl;
R1 is methoxy, ethoxy or a group OCH2CONH2, OCH2CH2OCH3, or
0(CH2)PNR4R5 where p is 2 or 3 and R4 and R5 are hydrogen, methyl, ethylor propyl or together R4 and R5 form a pyrrolidine, imidzole or morpholine
ring;
R2 is methoxy, ethoxy or 0(CH2)PNR4R5 where p is 2, 3 or 4 and R4 and R5 are hydrogen methyl or ethyl or one of R4 or R5 is mediyl and the other is pyridyl or pyrazole or R4 and R5 form a piperidine, hydroxypiperidine, thiomorpholine, morpholine, pyrrolidine, 2,6-dimethylmorpholine imidazole or triazole ring,
or a pharmaceutically acceptable salt or solvate thereof of the kind such as herein described,
• provided that when A is phenyl substituted by ethyl or propyl or disubstituted by methyl, then R1 and R2 are not both methoxy, R1 and R2 are not both ethoxy or one of RyR2 is not methoxy when the other is ethoxy.
2. A compound as claimed in claim wherein said
4(2-ethylanilino)-6-me1±ioxy-7-{2[methyl(4-pyridinyl)amino]ethoxy}-3-quinolinecarboxamide,
4-[3-(hydroxymethyl)-2-methylanilino]-6-methoxy-7-[3-(4-
thiomorpholinyl)propoxy]-3-quinolinecarboxamide
4-[3-(hydroxymethyl)-2-methylanilino]-6-methoxy-7-[3-(l-
piperidinyl) propoxy ] - 3 -quinolinecarboxamide,
4-[3-(hydroxymethyl)-2-methylanilino]-6-methoxy-7-[3-(4-
morpholinyl) propoxy] - 3 - quinolinecarboxamide,
7- [3- (dimethylamino) propoxy] -4- (2 -ethylanilino) -6-methoxy-3-quinoline
carboxamide,
7-[3-(dimethylamino)propoxy]-4-[3-hydroxymethyl)-2-methylanilino]-6-
methoxy- 3 -quinolinecarboxamide,
7-{3-[(2R,6S)-2,6-dimet±iylmorpholinyl]propoxy)-4-[3-(hydroxymethyl)-2-
methylanilino]-6-methoxy-3-quinolinecarboxamide,
4-(2-ethylanilino)-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-
quinolinecarboxamide,
4-(2-ethylanilino)-6-met±ioxy-7-[4-(4-morpholinyl)butoxy]-3-quinolinecar
boxamide,
4-(2- ethylanilino)-6-methoxy-7-{3-[methyl-(4-pyridinyl)amino)propoxy}-3-
quinolinecarboxamide,
4-(2- ethylanilino)-7-methoxy-6-[2-(methylamino)ethoxy]-3-
quinolinecarboxamide,
7-{3-[(2S,6S)-2,6-dimethylmorpholinyl]propoxy}-4-[3-(hydroxymethyl)-2-
methylanilino]-6-methoxy-3- quinolinecarboxamide,
4-(2-ethylanilino)-7-[3-(lH-imidazol-l-yl)propoxy]-6-methoxy-3-
quinolinecarboxamide,
6-(2-aminoet±ioxy)-4-(2-ethylanilino)-7-methoxy-3- quinolinecarboxamide,
6-methoxy-4-[2-(methylsulfanyl)anilino]-7-[3-(4-morpholinyl)propoxy]-3-
quinolinecarboxamide,
6-met±ioxy-7-(3-(4-morpholinyl)propoxy)-4-(2-toluidino)-3-
quinolinecarboxamide,
4-(2-ethylanilino)-6-methoxy-7-[3-( 1H-1,2,4-triazol- l-yl)propoxy]-3-
quinolinecarboxamide,
4-(2-ethylanilino)-6-methoxy-7-[2-(methylamino)ethoxy]-3-
quinolinecarboxamide,
4-(2-ethylanilino)-6-methoxy-7-(2-methoxyethoxy)-3-
quinolinecarboxamide,
4-(2-ethylanilino)-7-(3-hydroxypropoxy)-6-methoxy-3-
quinolinecarboxamide,
6-methoxy-7-[2-(4-moipholinyl)ethoxy)-4-(2-toluidino)-3-
quinolinecarboxamide,
4-[3-(hydroxyrnethyl)-2-methylanilino]-7-rnethoxy-6-[2-(l-pyrrolidinyl)
ethoxy)-3-quinolinecarboxamide,
3-[[3-(aminocarbonyl)-3,7-dimethoxy-4-quinolinyl]amino]-2-methylbenzoic
acid,
4-[3-(hydroxymethyl)-2-methylanilino-6,7-dimethoxy-3-quinolinecarboxa
mide,
4-(2-ethylanilino)-7-(2-(lH-imidazol-l-yl)et±ioxy]-6-methoxy-3-
quinolinecarboxamide,
4-[3-(2-hydroxyethyl)-2 -methylanilino)-6,7-dimethoxy-3-
quinolinecarboxamide,
7-methoxy-6-{[2-(4-moepholinyl)ethyl]amino}-4(2-toluidino)-3
quinolinecarboxamide,
4-(2-et±iylanilino)-6-[3-(lH-imidazol-l-yl)propoxy)-7-methoxy-3-
quinolinecarboxamide,
4-(2-ethylanilino)-7-methoxy-6-[2-( 1 -pyrrolidinyl)ethoxy)3-
quinolinecarboxarnide,
7-(3-aminopropoxy)-4-(2-ethylanilino)-6-methoxy-3-quinolinecarboxamide,
methyl 4-[[3-(aminocarbonyl)-6-methoxy-4-(2-toluidino)-7-
quinolinyl] oxy}butanoate,
4-[3-(aminomethyl)2-methylanilino]-6,7-dimethoxy-3-quinolinecarbo
xamide,
6-{[3-(lH-imidazol-l-yl)propyl]amino}-7-methoxy-4-(2-toluidino)-3-
quinolinecarboxamide,
4-[3-(hydroxyrnethyl)-2-rnethylanilino]-7-methoxy-6-(2-inethoxyethoxy)-3-
quinolinecarboxamide,
6-[2-(dimethylamino)ethoxy-[-4-(2-ethylanilino)-7-methoxy-3-
quinolinecarboxamide,
4-[3-(cyanomethyl)-2-methylanilino]-6,7-dimethoxy-3-quinolinecarbo
xamide,
4-[3-(2-amino-2-oxoethyl)-2-methylanilino]-6,7-dimethoxy-3-
quinolinecarboxamide,
6-(3-aminopropoxy)-4-(2-ethylanilino)-7-rnethoxy-3-quinolinecarboxamide.
4-[3-(hydroxymethyl)-2-methylanilino]-7-methoxy-6-[3-(4-
morpholinyl) propoxy] - 3 -quinolinecarboxamide,
4-[3-(hydroxyrnethyl)-2-methylanilino]-7-methoxy-6-[2-(4-
morpholinyl)ethoxy]-3-quinolinecarboxamide,
and pharmaceutical^ acceptable salts thereof.
3. A compound as claimed in claim wherein as compound is : 4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-(pyndine-4-ylamino) propoxy) quinoline- 3 -carboxamide, 4-[(2-ethylphenyl)amino]-7-methoxy-6-(3-[(2-amino-2-oxoethyl)amino]propoxy]-quinoline-3-carboxamide, 4-[(2-ethylphenyl)amino)-7-methoxy-6-[3-( 1 H-pyrazol-3-ylamino) propoxy] quinoline- 3 -carboxamide, 4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-(pyridin-2-ylamino) propoxy] quinoline- 3 -carboxamide,
Ethyl 4-[(3-(aminocarbony))-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinolin-7-yl)oxy]butanoate,
7-[3-(diethylamino)propoxy]-6-methoxy-4-[(2-methoxyphenyl)aminoquino line- 3 -carboxamide,
7-[3-(ethylamino)propoxy]-6-methoxy-4-{[2-(trifluoromethyl)phenyl]amino} quinoline-3-carboxamide,
7-[3-(ethylamino)propoxy)-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide,
4-[(2-ethylphenyl)amino]-7-3-(isopropylamino)propoxy]-6-methoxyquinoline-3-carboxamide,
7-[3-(ethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline- 3 -carboxamide,
4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(propylamino)propoxy]quinoline-3-carboxamide,
7-[3-(dirnethylainino)propoxy]-4-[(2-ethylphenyl)arnino]-6-methoxyquino
line-3-carboxamide,
4- [(2 -ethylphenyl)amino] -6-methoxy-7- (3- pyrrolidin-1 -ylpropoxy) quinoline-
3-carboxamide,
7-[3-(diethylarmino)propoxy)-4-[(2-ethylphenyl)arnino]-6-rnethoxyquinoline-
3- carboxamide,
4-[(2-ethylphenyl)amino]-6-methoxy-7-(3-piperidin-l-ylpropoxy)quinoline-
3-carboxamide,
7- [3 - (dimethy lamino) propoxy]-4{[2-ethy1-3-(hydroxymethy1)phenyl]amino}-
6- methoxyquinoline-3-carboxamide,
7-[3-(diethylamino)propoxy]-4-{[2-ethyl-3-(hydroxyrnethyl)phenyl]amino}-6-
methoxyquino1ine-3-carboxamide,
7-{3-[(2-ethoxyethyl)amino]propoxy}-4-[(2-ethylphenyl)amino]-6-
methoxyquinoline-3-carboxamide,
4-[(2-ethylphenyl)amino]-6-methoxy-7-(3-piperidin-l-ylpropoxy)quinoline-
3- carboxamide,
4-[(2-ethylphenyl)amino-6-methoxy-7-(3-thiomorpholin-4-
ylpropoxy)quinoline-3-carboxamid,
4-{[3-(hydroxyrnethyl)-2-methylphenyl]amino}-6-inethoxy-7-(3-pyrrolidin-l-
ylpropoxy)quinoline-3-carboxamide,
4-{[2-ethyl-3-(hydroxyrnethyl)phenyl]arnino}-6-methoxy-7-(3-pyrrolidin-l-
ylpropoxy)quinoline-3-carboxamide,
4-{[2-ethyl-.3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-(3-piperidin-l -
ylpropoxy)quinoline3-carboxamide,
4-{[3-(hydroxvrnethyl-2-rnethylphenyl]arnino}-7-[3-(3-hydroxypiperidin-l-
yl)propoxy-6-methoxyquinoline-3-carboxamide,
4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(lH-
1,2,4triazol-1 -yl)propoxy)quinoline-3-carboxamide,
and pharmaceutically acceptable salts thereof.
4. A pharmaceutical composition comprising a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier wherein the active compound is in a range of 0.1 mg/kg to l00mg/kg.
5. A process for the preparation of a compound of formula 1(a) as
claimed in claim 1 which comprises:
(a) reaction of a compound of formula (II):
(Formula Removed) in which R1 and R2 are as defined in formula (la) or are protected derivatives thereof and R20 is a leaving group, with a compound of formula (111):
(Formula Removed) in which Ar and R are as defined in formula (I) or are protected derivatives thereof prepared by either
• converting a compound of formula (la) into a further compound of
formula (la) by forming a pharmaceutically acceptable salt/
6. A process for the preparation of a compound as claimed in claim 1,
comprising:
(a) reaction of a compound of formula ((Ha):
(Formula Removed)
with a group L-CH2CONH2, L-CH2CH2OCH3, or L-(CH2)PNR4R5 wherein L is a leaving group and p is 2 or 3 and R4 and R5 are hydrogen, methyl, ethyl or propyl or together R4 and R5 form a pyrrolidine, imidazole or morpholine ring, prepared by either
• removing any protecting groups
converting a compound of formula (la) into a further compound of formula (la) by forming a pharmaly acceptable salt; or
(b) reaction of a compound of formula (IIba):
(Formula Removed) with a group L-(CH2)PNR4R5 wherein L a leaving group and 0(CH2)PNR4R5, p is 2, 3 or 4 and R4 and R5 are hydrogen, methyl or ethyl or one of R4 or R5 is methyl and the other is pyridyl or pyrazole or R4 and R5 form a piperidine, hydroxypiperidine, thiomorpholine, morpholine, pyrrolidine, 2,6-dimethylmorpholine imidazole or triazole ring followed as needed by • removing any protecting groups
converting a compound of formula (la) into a further compound of formula (la) by forming a pharmaceutically acceptable salt.


Documents:

1739-delnp-2003-abstract.pdf

1739-DELNP-2003-Claims.pdf

1739-delnp-2003-complete specification (as, file).pdf

1739-delnp-2003-complete specification (granted).pdf

1739-delnp-2003-correspondence-others.pdf

1739-delnp-2003-correspondence-po.pdf

1739-DELNP-2003-Description (Complete).pdf

1739-delnp-2003-form-1.pdf

1739-delnp-2003-form-19.pdf

1739-delnp-2003-form-2.pdf

1739-delnp-2003-form-3.pdf

1739-delnp-2003-form-4.pdf

1739-delnp-2003-form-5.pdf

1739-delnp-2003-gpa.pdf

1739-delnp-2003-pct-210.pdf

1739-delnp-2003-pct-304.pdf

1739-DELNP-2003-PCT-409.pdf

1739-delnp-2003-petition-137.pdf

abstract.jpg


Patent Number 244886
Indian Patent Application Number 1739/DELNP/2003
PG Journal Number 53/2010
Publication Date 31-Dec-2010
Grant Date 23-Dec-2010
Date of Filing 23-Oct-2003
Name of Patentee ASTRA ZENECA AB
Applicant Address S-151 85 SODERTALJE, SWEDEN
Inventors:
# Inventor's Name Inventor's Address
1 JOAKIM LARSSON ASTRAZENECA R & D, LUND, S-221 87, LUND SWEDEN
2 PETER SJO ASTRAZENECA R & D, LUND, S-221 87, LUND SWEDEN
PCT International Classification Number A61K 31/47
PCT International Application Number PCT/SE02/00875
PCT International Filing date 2002-05-06
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0101675.7 2001-05-11 Sweden