Use of cyanoquinolines for treating or inhibiting colonic polyps

专利摘要:
The present invention provides a method of treating or inhibiting a colonic polyp, including providing a compound of formula I or a pharmaceutically acceptable salt thereof. Formula I In the formula (I) R 1 , R 2 , R 3 , R 4 , X, Y and n are as defined in the specification.
公开号:KR20020092987A
申请号:KR1020027012074
申请日:2001-03-06
公开日:2002-12-12
发明作者:프로스트필립；디스카패니-매로캐롤린엠
申请人:아메리칸사이아나미드컴파니；
IPC主号:

专利说明:

Use of cyanoquinolines for the treatment or inhibition of colonic polyps {Use of cyanoquinolines for treating or inhibiting colonic polyps}
[1] The present invention relates to the use of certain cyanoquinoline compounds in the treatment and inhibition of colon polyps.
[2] Colon polyps occur both sporadically and in a familial manner (familial adenomatous polyps (FAP)). Approximately 25,000 patients in the United States suffer from FAP; There are approximately 2 million people in the United States alone each year with SAPs. All of these patients are at risk of developing colon cancer. In the case of FAP, this risk is virtually 100%, and these patients generally undergo colonic resection at an early stage. Patients with interstitial polyps are treated with polypectomy and periodic colonoscopy is required because of the inherent risks of re-emergence of polyps. In fact, parents and siblings of these patients are also at increased risk for developing colon cancer.
[3] The genetic basis for FAP is linked to mutations in the APC gene. Similar APC mutations were found in patients with interstitial polyps. Biochemically, APC mutations occur in association with increased expression of cyclooxygenase enzymes, particularly COX-2. These enzymes are essential for the production of prostanoids (prostaglandins: (PG)) that regulate multiple functions in the intestine, including intrinsic fluidity, vascular tone, angiogenesis and mucosal protection. PG also implies suppression of cell apoptosis and is proposed as described for polyp formation.
[4] FAP and SAP treatments have focused on COX enzyme inhibition. Significant evidence for this is the efficacy of COX inhibitors in reducing polyp formation. These COX inhibitors are NSAIDs, such as clinolyl, sulindac, piroxycam and etomoloc, all of which seem to be identical in their action.
[5] The major problems with NSAID therapy are severe side effects, including peptic ulcer, cholestatic hepatitis, and pneuropathic necrosis. Therefore, long-term therapy using NSAIDs for polyp therapy is considered unrealistic.
[6] Recently, the activity and overexpression of COX-2 in adenomatous polyps has been suggested due to the activity of epidermal growth factor receptor (EGFR). EGFR stimulation by one of its ligand-ampirirugulin (AR) causes nuclear drug targeting of COX-2, PG release and subsequent mitotic regeneration in the dividing colon epithelial cells. COX-2 inhibitors have been shown to prevent this series of conditions.
[7] DETAILED DESCRIPTION OF THE INVENTION
[8] The present invention provides a method of treating or inhibiting a colonic polyp of a mammal in need thereof, comprising providing an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a mammal in need of treating or inhibiting a colonic polyp do.
[9]
[10] In the formula (I)
[11] X is cycloalkyl having 3 to 7 carbon atoms which may optionally be substituted with one or more alkyl of 1 to 6 carbon atoms, or a pyridinyl, pyrimidinyl or phenyl ring wherein the pyridinyl, pyrimidinyl or phenyl ring is optionally substituted with halogen, Alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, azido, hydroxyalkyl having 1 to 6 carbon atoms, halomethyl, alkoxymethyl having 2 to 7 carbon atoms, alkanoyl having 2 to 7 carbon atoms Carbonyl having 2 to 7 carbon atoms, carboalkyl having 2 to 7 carbon atoms, phenoxyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, alkylthio having 1 to 6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, Benzyl, benzyl, amino, alkylamino of 1 to 6 carbon atoms, diacylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, alkanoylamino of 3 carbon atoms For eight of the alkenyl alkanoyl amino, optionally with a substituent selected from the group consisting of Al Keno ylamino and benzoylamino having 3 to 8 carbon atoms mono-substituted, may be substituted di or tri), and;
[12] n is 0 or 1;
[13] Y is -NH-, -O-, -S- or -NR-;
[14] R is alkyl having 1 to 6 carbon atoms;
[15] R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, halogen, alkyl having 1 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, alkenyloxy having 2 to 6 carbon atoms , Alkynyloxy having 2 to 6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy having 1 to 6 carbon atoms, alkenoyloxy having 3 to 8 carbon atoms, alkynoyloxy having 3 to 8 carbon atoms, alkynoyloxy having 2 to 7 carbon atoms Alkanoyloxymethyl having 4 to 9 carbon atoms, alkanoyloxymethyl having 4 to 9 carbon atoms, alkoxymethyl having 2 to 7 carbon atoms, alkoxy having 1 to 6 carbon atoms, alkylthio having 1 to 6 carbon atoms, Alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonamide of 1 to 6 carbon atoms, alkenylsulfonamido of 2 to 6 carbon atoms, alkynylsulfonamido of 2 to 6 carbon atoms, hydroxy , Trifluoromethyl, cyano, nitro, carboxy, carbon Carboalkoxy having 2 to 7 carbon atoms, carbonyl having 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino having 1 to 4 carbon atoms, alkylamino having 1 to 6 carbon atoms, Alkylaminoalkyl of 2 to 12 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, N-alkylaminoalkyl of 2 to 7 carbon atoms, N, N-dialkylaminoalkyl of 3 to 14 carbon atoms, phenylamino,
[16] , , , , , , , , , , , , , , , , or ego;
[17] R ₅ is C 1 -C 6 alkyl, optionally with one or more halogen atoms substituted alkyl, phenyl, or one or more halogen, C 1 -C 6 alkoxy, trifluoromethyl, amino, nitro, cyano or C 1 -C 6, Phenyl optionally substituted with an alkyl group;
[18] R ₆ is hydrogen, alkyl having 1 to 6 carbon atoms or alkenyl having 2 to 6 carbon atoms;
[19] R < ₇ > is chloro or bromo;
[20] R ₈ is selected from the group consisting of hydrogen, alkyl having 1 to 6 carbon atoms, aminoalkyl having 1 to 6 carbon atoms, N-alkylaminoalkyl having 2 to 9 carbon atoms, N, N-dialkylaminoalkyl having 3 to 12 carbon atoms, N-cycloalkylaminoalkyl, N-cycloalkyl-N-alkylaminoalkyl having 5 to 18 carbon atoms, N, N-dicycloalkylaminoalkyl having 7 to 18 carbon atoms, morpholino having 1 to 6 carbon atoms in the alkyl group -N-alkyl having 1 to 6 carbon atoms, piperidino-N-alkyl having 1 to 6 carbon atoms in the alkyl group, N-alkyl-piperidino-N-alkyl having 1 to 6 carbon atoms in the alkyl group, Alkyl, alkoxyalkyl of 2 to 8 carbons, carboxy, carboalkoxy of 1 to 6 carbons, phenyl, carbamoyl of 2 to 7 carbons, chloro, fluoro or bromo ;
[21] Z is amino, hydroxy, alkoxy having 1 to 6 carbon atoms, alkylamino having 1 to 6 carbon atoms in the alkyl moiety, dialkylamino having 1 to 6 carbon atoms in each alkyl moiety, morpholino, piperazino, alkyl Alkylpiperazino or pyrrolidino having 1 to 6 carbon atoms in the residue;
[22] m is from 1 to 4;
[23] q is 1 to 3;
[24] p is from 0 to 3;
[25] Adjacent substituent located at the carbon atom to R _1, R _2, R ₃ or R ₄ is taken together divalent be a radical -OC (R _{8) 2} -O-,
[26] With the proviso that when Y is -NH- and R ₁ , R ₂ , R ₃ and R ₄ are hydrogen and n is 0, then X is not 2-methylphenyl.
[27] Pharmaceutically acceptable salts include those salts with organic acids such as acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, malonic acid, gluconic acid, hydrochloric acid, bromic acid, phosphoric acid, nitric acid, Organic and inorganic acids.
[28] Alkyl, alkanoyloxy, alkoxymethyl, alkanoyloxymethyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, carboalkoxy, carboalkyl, alkanoylamino, aminoalkyl, alkylaminoalkyl, N, N- The alkyl moieties of the dicycloalkylaminoalkyl, hydroxyalkyl and alkoxyalkyl substituents include both linear and branched carbon chains. The N-cycloalkyl-N-alkylaminoalkyl and the cycloalkyl portion of the N, N-dicycloalkylaminoalkyl substituent include both a simple carbocycle and an alkyl substituent containing carbocycle. The alkenyl moieties of the alkenyl, alkenoyloxymethyl, alkenyloxy, alkenylsulfonamido substituents include both linear and branched carbon chains, and at least one unsaturation position. The alkynyl moiety of the alkynyl, alkynoyloxymethyl, alkynylsulfonamido, alkynyloxy substituents includes both linear and branched carbon chains, and at least one unsaturation position. Carboxy, it is defined as a -CO ₂ H radical. Having 2 to 7 carbon atoms in the alkoxy kabok is -CO ₂ R "radical (wherein, R" is an alkyl radical having 1 to 6 carbon atoms) is defined as. Carboalkyl is defined as a -COR " radical, where R " is an alkyl radical of one to six carbon atoms. Alkanoyloxy is defined as a -OCOR " radical, wherein R " is an alkyl radical of one to six carbon atoms. Alkanoyloxymethyl is defined as R " CO ₂ CH ₂ - radical where R "is an alkyl radical having 1 to 6 carbon atoms. Alkoxymethyl are R "OCH ₂ - radical (wherein, R" is an alkyl radical having 1 to 6 carbon atoms) is defined as. The alkylsulfinyl is defined as the R " SO- radical, wherein R " is an alkyl radical of one to six carbon atoms. Alkylsulfonyl R "SO ₂ - radical (wherein, R" is an alkyl radical having 1 to 6 carbon atoms) is defined as. Alkylsulfonamido, alkenylsulfonamido and alkynylsulfonamido are R "SO ₂ NH-radicals wherein R" is an alkyl radical of 1 to 6 carbon atoms, an alkenyl radical of 2 to 6 carbon atoms or an alkyl radical of 2 to 6 carbon atoms, Lt; / RTI > to 6). N-alkylcarbamoyl is defined as R " NHCO-radical where R " is an alkyl radical of one to six carbon atoms. N, N-dialkylcarbamoyl is a radical of the formula R "R'NCO-radical where R" is an alkyl radical of 1 to 6 carbon atoms, R 'is a radical of 1 to 6 carbon atoms, R' and R " When X is substituted, it is preferably monosubstituted, disubstituted or trisubstituted, and most preferably monosubstituted. When at least one of substituents R ₁ , R ₂ , R ₃ and R ₄ Most preferably, two or three are hydrogen, the azacycloalkyl-N-alkyl substituent represents a monocyclic heterocycle containing a nitrogen atom substituted by a substituted straight or branched alkyl radical. N-alkyl substituents are morpholine rings wherein the nitrogen atom is replaced by a straight or branched alkyl radical. A piperidino-N-alkyl substituent is a piperidine ring wherein one nitrogen atom is replaced by a straight chain or branched alkyl radical. -Alkyl-piperidino-N-alkyl < / RTI > Hwanche is substituted on one nitrogen atom with a straight or branched chain alkyl groups or other nitrogen atom optionally substituted with straight or branched chain alkyl radicals piperidine ring.
[29] The compounds of the present invention may contain asymmetric carbons; In this case, the compounds of the present invention comprise racemate and each R and S enantiomer, in which case there is at least one asymmetric carbon, each diastereomer, their racemate and each enantiomer .
[30] As used according to the present invention, the term effective amount means to administer the compound of the present invention directly to the body, or to administer to the body a prodrug, derivative or analogue which will form an effective amount of the compound of the present invention.
[31] The process for preparing the compounds of the present invention defined by formula 5 is illustrated by the following reaction scheme A:
[32]
[33] In Scheme A above,
[34] Y and n are as defined above,
[35] X 'is hydrogen, halogen, alkyl having 1 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, halomethyl, alkoxy having 1 to 6 carbon atoms, alkylthio having 1 to 6 carbon atoms, Cycloalkyl optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, Or phenyl.
[36] R ₁ ', R ₂ ', R ₃ 'and R ₄ ' each independently represents hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, Alkenyloxy of 2 to 6 carbon atoms, alkynyloxy of 2 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, Alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonamido of 1 to 6 carbon atoms, trifluoromethyl, cyano, nitro, carboxy, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, Dialkylamino having 2 to 12 carbon atoms, N, N-dialkylaminoalkyl having 3 to 14 carbon atoms, phenylamino, benzylamino, N-alkylcarbamoyl having 1 to 6 carbon atoms, Lt; / RTI > to N, N-dialkylcarbamoyl. Some of the substituents R ₁ ', R ₂ ', R ₃ 'or R ₄ ' located at adjacent carbon atoms may together be a bivalent radical -OC (R ₈ ) ₂ -O-. According to the reaction sequence outlined in Scheme A, the quinoline-3-carboxylic acid ester of formula (2) is hydrolyzed with the base to produce the carboxylic acid of formula (3). The carboxylic acid group of formula (3) is converted to the acyl imidazole by heating with carbonyldiimidazole in an inert solvent such as dimethylformamide (DMF), followed by the addition of ammonia to give amide (4). The amide functional group is dehydrated using a dehydrating agent such as trifluoroacetic anhydride in pyridine, phosphorus pentoxide in an inert solvent or the like to obtain 3-cyanoquinoline (5) of the present invention. If some of the intermediates have an asymmetric carbon atom, these compounds may be used as racemates or as respective R or S enantiomers, where the compounds of the present invention may be racemic or R and S optically active forms. The quinoline-3-carboxylic acid ester of formula 2, the quinoline-3-carboxylic acid of formula 3 and the quinoline-3-carboxylic acid amide of formula 4 required to prepare the compounds of the present invention are either already known in the art, : Sarges, Reinhard; Gallagher, Andrea; Chambers, Timothy J .; Yeh, Lien, J. Med. Chem., 36, 2828 (1993); Savini, Luisa; Massarelli, Paola; Pellerano, Cesare; Bruni, Giancarlo, Farmaco, 48 (6), 805 (1993); Ife, Robert J .; Brown, Thomas H .; Keeling, David J .; Leach, Colin, J. Med. Chem., 35, 3413 (1992); Hanifin, J. William; Capuzzi, Rosemary; Cohen, Elliott, J. Med. Chem., 12 (5), 1096 (1969); Marecki, Paul E .; Bambury, Ronald E., J. Pharm. Sci., 73 (8), 1141 (1984); Pellerano, C .; Savini, L .; Massarelli, P .; Bruni, G .; Fiaschi, AI, Farmaco, 45 (3), 269, (1990); Marecki, Paul E .; Bambury, Ronald E., J. Pharm, Sci., 73 (8), 114 (1984); International Patent Publication No. WO 8908105; U.S. Pat. No. 4,343,804 and U.S. Pat. No. 3,470,186, the disclosures of which are incorporated herein by reference.
[37] The process for preparing the compounds of the present invention defined by formulas (10) and (11) is illustrated by the following reaction scheme B:
[38]
[39] In Scheme B above,
[40] Y, p and n are as defined above.
[41] X "is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms , Alkoxy having 1 to 6 carbon atoms, alkylthio having 1 to 6 carbon atoms, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy having 2 to 7 carbon atoms, carboalkyl having 2 to 7 carbon atoms, phenoxy, Benzoyl, benzoyl, diacylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms and it is optionally selected from the group consisting of substituted cycloalkyl, or phenyl with at least one substituent selected from the group consisting of benzoylamino. each R ₉ is independently hydrogen, phenyl or alkenyl group having 1 to 6 carbon atoms A. Residue (R _{10) k} represent 1 to 3 substituents on the aromatic ring, which may be the same or different, hydrogen, halogen, C 1 -C 6 alkyl, alkenyl of 2 to 6 carbon atoms, having 2 to Alkynyl of 6 to 6 carbon atoms, alkenyloxy of 2 to 6 carbon atoms, alkynyloxy of 2 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, A carbamoyl group having 1 to 6 carbon atoms, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, a trifluoromethyl group, a cyano group, a nitro group, N-dialkylaminoalkyl having 3 to 14 carbon atoms, phenylamino, benzylamino, N-alkylcarbamoyl having 1 to 6 carbon atoms, alkoxyamino having 2 to 12 carbon atoms, alkoxyamino having 1 to 4 carbon atoms, dialkylamino having 2 to 12 carbon atoms, 12 < / RTI > N, N-dialkylcarbamoyl R < ₁₁ > is independently selected from , , , , , , , , , And It is a radical selected from the group consisting of _{(wherein, q, R 5, R 6} , R 7 and R ₈ are the same as defined above). According to the reaction sequence outlined in scheme B, the compound of formula 6 is reacted with an organic base such as pyridine, triethylamine or N-methylmorpholine (Prepared from the corresponding carboxylic acid) in the presence of an acid chloride of formula 8 in an inert solvent such as tetrahydrofuran (THF) When the compound of formula 8 or 9 has an asymmetric carbon, these compounds may be prepared by reacting racemate or a respective R or S < RTI ID = 0.0 > Can be used as the enantiomer. The compound of formula 6 is reacted in the presence of a basic catalyst (e.g. pyridine or triethylamine) in an inert solvent (e.g. tetrahydrofuran) Acylation using a cyclic anhydride gives the compounds of the present invention represented by formula 10. Compounds of formula 6 wherein p is 0 can be prepared by reacting a nitro group with iron or ammonium chloride in an alcohol, Can be prepared from an aromatic nitro-substituted compound by reduction using a reducing agent such as sulfite.
[42] The method of making the included inventive compounds defined by formula 18 is illustrated by the following scheme C:
[43]
[44] In Scheme C above,
[45] X, Y, n, R ₁ ', R ₂ ', R ₃ 'and R ₄ ' are as defined above.
[46] Substituted aniline of formula (12) is heated using reagent (13) in the presence or absence of a solvent to obtain intermediate (14) as an isomeric mixture. Obtaining a 3-cyanoquinolone of formula (15) by decomposition of intermediate (14) in a solvent which is boiling under 200 to 350 占 폚, such as diphenyl; Such an intermediate may be present in the form of a 4-hydroxyquinoline tautomer. When R ₄ 'is a hydrogen atom, the intermediate (15) can be formed as a mixture of two zone isomers. These isomers can be separated by methods well known in the art, including, but not limited to, fractional crystallization and chromatographic methods. Thereafter, the separated isomers can be individually converted into the compounds of the present invention. Further, the isomer may be separated after the synthesis step. The compound of formula (15) is heated in the presence or absence of a solvent using a chlorinating agent such as phosphorus oxychloride or contamination to give 4-chloro-3-cyanoquinoline of formula (16). The compound of formula 16 is condensed with a nucleophilic amine, aniline, mercaptan, thiophenol, phenol or an alcohol reagent of formula 17 to give the 3-cyanoquinoline of formula 18, Or may be promoted by using trialkylamine or sodium hydroxide in an inert solvent, sodium alkoxide or potassium alkoxide in an alcohol solvent, or the like. When the substituent, X, R ₁ ', R ₂ ', R ₃ 'and R ₄ ' can contribute to an asymmetric carbon atom, the intermediates can be prepared by reacting the compounds of the invention with racemic or R and S, Can be used as racemate or as each R or S enantiomer. When the substituents X, R ₁ ', R ₂ ', R ₃ 'and R ₄ ' can contribute to one or more asymmetric carbon atoms, diastereomers may be present; These may be separated by methods well known in the art, including, but not limited to, fractional crystallization and chromatographic methods.
[47] Intermediate 21 [identical to intermediate (15) in Scheme C] can also be prepared as described in Scheme D below:
[48]
[49] The substituted aniline of formula 19 is heated in the presence or absence of a solvent using dimethylformamide dimethylacetal to give an intermediate of formula 20. Reacting a compound of formula 20 with 1 to 10 equivalents of acetonitrile using a base such as sodium methoxide in an inert solvent to give 3-cyanoquinoline (21), or using the process outlined in Scheme C 3-cyano-4-hydroxyquinoline tautomer of intermediate (21) which can be converted into the compound of the present invention is obtained.
[50] Compounds of formula 22 wherein R ₁ , R ₂ , R ₃ , R ₄ , n and X 'are as defined above are as follows:
[51]
[52] When at least one of R ₁ , R ₂ , R ₃ or R ₄ in formula (22) is a nitro group, it can be converted to the corresponding amino group by reduction with acetic acid using a reducing agent such as iron.
[53] When at least one of R ₁ , R ₂ , R ₃ or R ₄ in formula (22) is an amino group, by alkylating at least 2 equivalents of an alkyl halide having 1 to 6 carbon atoms by heating in an inert solvent, Dialkylamino groups.
[54] When at least one of R ₁ , R ₂ , R ₃ or R ₄ in the formula (22) is a methoxy group, it may be reacted with a demethylating agent such as boron tribromide in an inert solvent, Can be converted to the corresponding hydroxy group by heating with chloride.
[55] When at least one of R ₁ , R ₂ , R ₃ or R ₄ in formula (22) is an amino group, an alkylsulfonyl chloride, alkenylsulfonyl chloride or alkenylsulfonyl chloride, Naphthylsulfonyl chloride, respectively, to the corresponding alkylsulfonamido, alkenylsulfonamido or alkynylsulfonamido group having 2 to 6 carbon atoms. When at least one of R ₁ , R ₂ , R ₃ or R ₄ in formula (22) is an amino group, the reagent Cl-C (R ' ₆ ) is reacted with an excess of an organic base such as triethylamine in an inert solvent. ₂ -CHR ₆ 'SO ₂ Cl, wherein R ₆ ' is hydrogen or alkyl of 1 to 4 carbon atoms, to the corresponding alkenylsulfonamido group.
[56] If two of the formula 22 R _1, R _2, R ₃ or R ₄ is adjacent methoxy group, the corresponding compound contiguous with a hydroxy group or by using a demethylating agent such as boron tribromide in an inert solvent, ≪ / RTI > can be prepared by heating with pyridinium chloride with or without a solvent.
[57] When two of R ₁ , R ₂ , R ₃ or R ₄ in formula (22) are adjacent hydroxy groups, they may be reacted with a base such as cesium carbonate or potassium carbonate in an inert solvent and, if necessary, R _{8) 2} -J- (wherein, J is the same or different chloro, bromo or iodo a) the reaction by the two adjacent R _1, R _2, R ₃ or R ₄ is a divalent group OC (R along each ₈ ) _2- O wherein R ₈ is as defined above.
[58] When at least one of R ₁ , R ₂ , R ₃ or R ₄ in formula (22) is an amino group, it is alkylated with 1 equivalent of an alkyl halide having 1 to 6 carbon atoms by heating in an inert solvent, or with water or an alcohol, Can be converted to the corresponding alkylamino group having 1 to 6 carbon atoms by reductive alkylation of an aldehyde having 1 to 6 carbon atoms with a reducing agent such as sodium cyanoborohydride in a polar solvent such as a mixture of acetonitrile and water.
[59] When at least one of R ₁ , R ₂ , R ₃ or R ₄ in formula (22) is hydroxy, by reacting with a suitable carboxylic acid chloride, anhydride or mixed anhydride using pyridine or trialkylamine as catalyst in an inert solvent, To an alkanoyloxy group having 1 to 6 carbon atoms.
[60] When at least one of R ₁ , R ₂ , R ₃ or R ₄ in formula (22) is hydroxy, by reacting with a suitable carboxylic acid chloride, anhydride or mixed anhydride using pyridine or trialkylamine as catalyst in an inert solvent, To an alkenoyloxy group having 1 to 6 carbon atoms.
[61] When at least one of R ₁ , R ₂ , R ₃ or R ₄ in formula (22) is hydroxy, by reacting with a suitable carboxylic acid chloride, anhydride or mixed anhydride using pyridine or trialkylamine as catalyst in an inert solvent, To an alkynoyloxy group having 1 to 6 carbon atoms.
[62] When at least one of R ₁ , R ₂ , R ₃ or R ₄ in formula (22) is carboxy or a carboalkoxy group having 2 to 7 carbon atoms, said group may be suitably selected from the group consisting of borane, lithium borohydride or lithium aluminum hydride Can be converted to the corresponding hydroxymethyl group by reduction using a reducing agent, and again, in order to provide a phosphorus tribromide or chloromethyl group to obtain a bromomethyl group in an inert solvent, a halogenating reagent Lt; RTI ID = 0.0 > halomethyl < / RTI > group. The hydroxymethyl group may be optionally substituted with one or more substituents selected from the group consisting of an alkanoyloxymethyl group having 2 to 7 carbon atoms, an alkanoyloxymethyl group having 2 to 7 carbon atoms or an alkanoyloxymethyl group having 2 to 7 carbon atoms Can be acylated with a suitable acid chloride, anhydride or mixed anhydride using pyridine or trialkylamine as catalyst in an inert solvent.
[63] When at least one of R ₁ , R ₂ , R ₃ or R ₄ in formula (22) is a halomethyl group, the alkoxymethyl group can be converted into an alkoxymethyl group having 2 to 7 carbon atoms by substituting a hydrogen atom in the inert solvent with a sodium alkoxide.
[64] When at least one of R ₁ , R ₂ , R ₃ or R ₄ in the formula (22) is a halomethyl group, by substituting the halogen atom with ammonia, a primary amine or a secondary amine in an inert solvent, To an N-alkylaminomethyl group of 7 to 7 carbon atoms or an N, N-dialkylaminomethyl group of 3 to 14 carbon atoms.
[65] When at least one of R ₁ , R ₂ , R ₃ or R ₄ in formula (22) is an H ₂ N (CH ₂ ) _p - group, in order to obtain an isocyanate, in the presence of a base such as pyridine, Or by treating with an excess of the alcohol R ₅ -OH or the amine R ₅ -NH ₂ or (R ₅ ) ₂ NH, respectively, , or (Wherein R < ₅ > and p are as defined above).
[66] When at least one of R ₁ , R ₂ , R ₃ or R ₄ in formula (22) is an HO- (CH ₂ ) _p - group, suitable alkyl or phenyl chloroformates, R ₅ -OCOCl, alkyl or phenyl substituted isocyanate, R ₅ -N = C = O, alkyl or phenyl substituted carboxylic acid chloride, or R ₅ -COCl, , or (Wherein R < ₅ > and p are as defined above).
[67] When at least one of R ₁ , R ₂ , R ₃ or R ₄ in formula (22) is an HO (CH ₂ ) _p - group, reaction with reagent (R ₅ ) ₂ NCOCl in an inert solvent using a basic catalyst such as pyridine Lt; RTI ID = 0.0 > (Wherein R < ₅ > and p are as defined above).
[68] The ability of the compounds of the invention to treat or inhibit colonic polyps has been demonstrated by standard pharmacological test procedures in vivo as described below. The compound of Example 339 was evaluated by this procedure, which is comparable to human familial adenomatous polyposis (FAP) as a representative compound of the present invention. The most recent useful model for FAP, the min mouse, used in the testing process, is the loss of both transcripts of the APC gene. These animals develop a variety of intestinal polyps (adenomas). The polyp arising in a minus mouse expresses EGFR and has activated COX-2. NSAIDs such as sulindac and etostaroc may reduce (but not eradicate) long-polyps in these animals, indicating that the ultimate production of COX-2 and PG is likely to be responsible for this effect. The procedure used and results obtained in the standard pharmacological test procedure are briefly described below.
[69] The compound of Example 399 is blended with a standard mouse solid feed and the animals are randomly accessed for 60 days. Based on the measured food consumption, the compound of Example 339 is added at a concentration equivalent to an animal intake of 5 mg / kg / day or 150 mg / kg / day. On day 61, 10-15 animals are sacrificed in each treatment group + 10-15 control (solid feed only) animals corresponding to each treatment group, and the number of polyps is assessed. Table 1 summarizes the results.
[70] Test groupMean number of polyps ± standard deviationP-value vs. controlGroup I Control 5 mg / kg / day - Example 39932.6 ± 19.115.6 ± 6.0p = 0.01Group II Control 150 mg / kg / day - Example 39919.5 ± 14.12.6 ± 1.6p < 0.001
[71] These data demonstrate that the compounds of the present invention effectively inhibit polyp formation in animals having mutations in their APC genes. Based on the results obtained in this standard pharmacological test procedure, the compounds of the present invention are useful for treating or inhibiting colon polyp formation.
[72] The performance of EGFR kinase inhibitors to treat or inhibit colonic polyps is demonstrated by the use of (4-dimethylamino-but-2-enoic acid [4- (3-chloro-4- - phenylamino) -3-cyano-7-ethoxy-quinolin-6-yl] -amide as an inhibitor of EGFR kinase inhibition. (4-Dimethylamino- The preparation and activity of [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-ethoxy-quinolin-6-yl] -amide are described in U.S. Patent No. 6,002,008 This strong EGFR kinase inhibitor, (4-dimethylamino-but-2-enoic acid [4- (3-chloro-4- fluoro-phenylamino) -3-cyano-7-ethoxy-quinoline -6-yl] -amide has been shown to be effective in significantly reducing the number of polyps in mice.
[73] The procedure described below is comparable to that of a human familial adenomatous polyp (FAP) using a minus mouse (C57BL / 6J-min / +), a mutant mouse species in the APC (adenomatous polyposis coli) gene. When anemia or intestinal suppression results from high fat foods that eventually die at a lifetime of 120 days, these animals develop many long polyps (adenomas). A polyp that develops in a minus mouse expresses EGFR and has activated COX-2. The procedure used and results obtained in the standard pharmacological test procedure are briefly described below.
[74] The test animals are divided into two treatment groups: Group I, control and Group II, (4-dimethylamino-but-2-enoic acid [4- (3-chloro-4-fluoro- 6-yl] -amide. The test compounds administered to Group II were blended with AIN-93G mouse solid diet (Bioserve, New Jersey, Frenchtown) and the animals were anesthetized Approximately 20 mg / kg of (4-dimethylamino-but-2-enoic acid [4- (3- chloro-4-fluoro- phenylamino) -3-cyano-7-ethoxy-quinolin- ; -... is optionally accessible to the amount of food corresponding to the amide to treat the animals for 60 days, weighed once a day per week to food by measuring the consumption, and the animals also weighed weekly for 61 days, the CO ₂ Euthanize by inhaling and remove the entire intestine from the anus to the anus.Inject the Bouins fixative into the intestine and fix it for a few days.Then, ., And measuring the number of polyps to stew deoncheu using t- test for statistical analysis: 0.05 p- value of less than or equal is considered to be significant statistically.
[75] The results obtained in Table 2 are summarized.
[76] Treatment groupNumber of polypsP value Group I19.5 ± 14.1Group II2.6 ± 1.6<0.001
[77] The results obtained in this standard pharmacological test procedure show that (4-dimethylamino-but-2-enoic acid [4- (3-chloro-4-fluoro-phenylamino) -3-cyano- Quinolin-6-yl] -amide showed a 87% reduction in polyp number when comparing only AIN-93G control food.
[78] The compounds of the present invention may be formulated neat or admixed with one or more pharmaceutically acceptable carriers for administration. For example, solvents, diluents, etc. may be formulated into tablets, capsules, dispersible powders, suspensions containing, for example, about 0.05 to 5% of a particulate agent, for example, about 10 to 50% Syrup and elixirs containing, for example, about 20 to 50% ethanol, or may be administered orally in a sterile injectable solution or suspension formulation containing about 0.05 to 5% of a suspending agent in isotonic medium can do. Such pharmaceutical formulations may contain, for example, from about 0.05 to about 90%, more usually from about 5 to 60% by weight, of the active ingredient, mixed with the carrier.
[79] The effective amount of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. In general, however, when the compound of the present invention is administered in an amount of about 0.5 to about 1000 mg per animal body weight per day in a daily dose, in a dosage of 2 to 4 divided doses per day, or in a sustained form, . For the largest mammals, the total daily dose is from about 1 to 1000 mg, preferably from about 2 to 500 mg. Suitable dosage forms for enteral use include about 0.5 to 1000 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. Such dosage regimens may be adjusted to provide optimal therapeutic response. For example, several divided doses may be administered daily, or the dosage may be proportionally reduced as indicated by the urgency of the treatment situation.
[80] The compounds of the present invention can be administered orally as well as intravenously, intramuscularly or subcutaneously. The solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while the liquid carriers include sterilized water, polyethylene glycol, beeswax, Anionic surfactants, and edible oils such as corn oil, peanut oil and sesame oil. It would be advantageous for the adjuvants conventionally used in the manufacture of pharmaceutical compositions to include spices, colorants, preservatives and antioxidants such as vitamin E, ascorbic acid, BHT and BHA.
[81] Preferred pharmaceutical compositions in terms of ease of manufacture and administration are solid compositions, especially tablets and hard-filled or liquid-filled capsules. It is preferable to orally administer the compound.
[82] In some cases, it may be desirable to administer the compound directly to the medicament by airway in the form of an aerosol.
[83] The compounds of the present invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as free bases or pharmaceutically acceptable salts may be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions may also be prepared from glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under conventional storage and application conditions, these formulations contain preservatives to prevent the growth of microorganisms.
[84] Pharmaceutical formulations suitable for injectable use include sterile aqueous solutions or dispersions, and disinfecting powders for temporary preparation of sterile injectable solutions or dispersions. In all cases, the formulation should be sterile and should be fluid to the extent that it is easily injectable. It must be stable under the conditions of manufacture and storage and must be protected against the contamination behavior of microorganisms such as bacteria and fungi. The carrier may be, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), a suitable mixture thereof, and a solvent or dispersion liquid containing edible oil.
[85] For the treatment of cancer, the compounds of the present invention may be administered in combination with other anticancer agents or radiation therapy. Other substances or radiation therapies may be provided at the same time or at different times as the compounds of the present invention. These mixed therapies will work synergistically to improve efficacy. For example, the compounds of the present invention may be used in combination with a mitotic inhibitor such as Taxol or vinblastine, an alkylating agent such as cisplatin or cyclophosphamide, a metabolic antagonist such as 5-fluorouracil or hydroxyurea, an adriamycin or bleomycin, A topoisomerase inhibitor such as etoposide or camptothecin, or an antiestrogen agent such as tamoxifen.
[86] Methods for the preparation of representative examples of the compounds of the present invention are described below.
[87] Example 1
[88] Dihydro-7-methoxy-4-oxo-3-quinolinecarbonitrile
[89] A mixture of 30.2 g (245.2 mmol) of 3-methoxyaniline and 41.5 g (245.2 mmol) of ethyl (ethoxymethylene) cyanoacetate was heated at 140 ° C for 30 minutes in the absence of solvent. Add 1200 mL of Dowtherm to the resulting oil. The solution is refluxed with stirring under nitrogen for 22 hours. The mixture is cooled to room temperature and the solid is collected and washed with hexane. The solid was recrystallized from acetic acid to give 17 g of 1,4-dihydro-7-methoxy-4-oxo-3-quinolinecarbonitrile: Mass spectrum (electrospray, m / e): M + H 200.9.
[90] Example 2
[91] 4-Chloro-7-methoxy-3-quinolinecarbonitrile
[92] A mixture of 4.0 g (20 mmol) of 1,4-dihydro-7-methoxy-4-oxo-3-quinolinecarbonitrile and 8.3 g (40 mmol) of fouling is heated at 165 DEG C for 3 hours. The mixture is diluted with hexane and the solid is collected. The solid is mixed with brine and dilute sodium hydroxide solution and then extracted several times with a mixture of tetrahydrofuran and ethyl acetate. The solution was dried over magnesium sulfate and filtered through a pad of silica gel to give 3.7 g of 4-chloro-7-methoxy-3-quinolinecarbonitrile as a white solid: Mass spectrum (electrospray, m / e) M &lt; + &gt; H 218.9.
[93] Example 3
[94] 4 - [(3-bromophenyl) amino] -7-methoxy-3-quinolinecarbonitrile
[95] A solution of 2.97 g (13.6 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile and 4.67 g (27.2 mmol) of 3-bromoaniline in 76 ml of methoxyethanol is refluxed under nitrogen for 5 hours. The solution is cooled and then diluted with ether. The solid is collected and washed with ether. The solid is stirred with a hot mixture of ethyl acetate and sodium bicarbonate solution. The organic layer is separated and dried with magnesium sulfate. The solvent was removed and the residue was recrystallized from a chloroform-ethyl acetate mixture to give 1.6 g of 4 - [(3-bromophenyl) amino] -7-methoxy-3-quinolinecarbonitrile as a white solid: Mass spectrum (electrospray, m / e): M + H 354.1, 356.1.
[96] Example 4
[97] Dihydro-7-methoxy-6-nitro-4-oxo-3-quinolinecarbonitrile
[98] 6 g (74.9 mmol) of ammonium nitrate are added to a suspension of 10 g (49.6 mmol) of 1,4-dihydro-7-methoxy-4-oxo-3-quinolinecarbonitrile in 160 ml of trifluoroacetic anhydride over 3 hours. The mixture is further stirred for 2 hours. The excess anhydride is removed at 45 [deg.] C under reduced pressure. The residue is stirred with 500 mL of water. The solid is collected and washed with water. The solids are dissolved in 1000 mL of boiling acetic acid and the solution is treated with decolorizing charcoal. The mixture is filtered and concentrated to a volume of 300 mL. The collected solid was cooled to give 5.4 g of 1,4-dihydro-7-methoxy-6-nitro-4-oxo-3-quinolinecarbonitrile as a brown solid: mass spectrum (electrospray, m / e ): M &lt; + &gt; H 246.
[99] Example 5
[100] 4-chloro-7-methoxy-6-nitro-3-quinolinecarbonitrile
[101] A mixture of 5.3 g (21.6 mmol) of 1,4-dihydro-7-methoxy-6-nitro-4-oxo-3-quinolinecarbonitrile and 9 g (43.2 mmol) . The mixture is diluted with hexane and the solids are collected. The solid is dissolved in 700 mL of ethyl acetate and washed with cold dilute sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel to give 5.2 g of 4-chloro-7-methoxy-6-nitro-3-quinolinecarbonitrile as a tan solid.
[102] Example 6
[103] 4 - [(3-bromophenyl) amino] -7-methoxy-6-nitro-3-quinolinecarbonitrile
[104] A solution of 5.2 g (19.7 mmol) of 4-chloro-7-methoxy-6-nitro-3-quinolinecarbonitrile and 3.7 g (21.7 mmol) of 3-bromoaniline in 130 ml of methoxyethanol is refluxed under nitrogen for 4 hours . The reaction mixture is poured into dilute sodium bicarbonate solution. The solid is collected, washed with water and then dried in air. The solid is chromatographed on silica gel eluting with chloroform-ethyl acetate (9: 1). Removal of the solvent from the product fractions gave 1.2 g of 4 - [(3-bromophenyl) amino] -7-methoxy-6-nitro-3-quinolinecarbonitrile as a yellow solid: mass spectrum m / e): M + H 399.0, 402.0.
[105] Example 7
[106] Amino-4 - [(3-bromophenyl) amino] -7-methoxy-3-quinolinecarbonitrile
[107] 2.05 g (5.1 mmol) of 4 - [(3-bromophenyl) amino] -7-methoxy-6-nitro- ) Is stirred under reflux in 26 mL of water and 26 mL of methanol for 2 hours. The mixture is diluted with dilute ethyl acetate and the hot mixture is filtered. The organic layer is separated from the filtrate and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on silica gel, eluting with a mixture of chloroform and ethyl acetate. The product fractions were combined to give 1.3 g of 6-amino-4 - [(3-bromophenyl) amino] -7-methoxy-3-quinolinecarbonitrile as a yellow solid: Mass Spectrum ): M &lt; + &gt; H 369.1, 371.1.
[108] Example 8
[109] N- [4 - [(3-bromophenyl) amino] -3-cyano-7-methoxy-6-quinolinyl]
[110] 3.1 g (3.4 mmol) of N-methylmorpholine are added to a solution of 1.44 g (17.14 mmol) of 2-butynoic acid and 2.26 g (16.5 mmol) of isobutyl chloroformate in 30 ml of tetrahydrofuran with stirring at 0 ° C. The mixed anhydride solution was added to 1.13 g (3.06 mmol) of a 6-amino-4 - [(3-bromophenyl) amino] -7-methoxy-3-quinolinecarbonitrile suspension in 30 mL of tetrahydrofuran over 24 hours It is added in three divided portions. The solvent is removed. The residue is stirred with dilute sodium bicarbonate solution. The solid is collected and washed with water and ether. This is recrystallized from 1-butanol. The resulting solid is dissolved in hot tetrahydrofuran and filtered through silica gel. The filtrate was concentrated and diluted with hexane to give N- [4 - [(3-bromophenyl) amino] -3-cyano-7-methoxy-6-quinolinyl] 0.71 g: mass spectrum (electrospray, m / e): M + H 437.1, 438.1.
[111] Example 9
[112] N- [4- [(3-bromophenyl) amino] -3-cyano-7-methoxy-6-quinolinyl] -2-propenamide
[113] (4.06 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -7-methoxy-3-quinolinecarbonitrile and 0.45 mL of N-methylmorpholine in 30 mL of tetrahydrofuran under nitrogen 0.42 g (4.7 mmol) of acryloyl chloride is added over 15 minutes while stirring at 0 占 폚. After 1 hour at 0 C, the solution is diluted with 200 mL of ethyl acetate. The mixture is washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. The solvent is removed. The residue was chromatographed on silica gel, eluting with a chloroform-ethyl acetate mixture, to give 0.5 g of the title compound as a light yellow solid powder: Mass spectrum (electrospray, m / e): M + H 423.1, 425.1.
[114] Example 10
[115] 2-Cyano-3- (4-nitrophenylamino) acrylic acid ethyl ester
[116] 4-Nitroaniline (60.0 g, 0.435 mol) and ethyl (ethoxymethylene) cyanoacetate (73.5 g, 0.435 mol) are mechanically mixed in a flask. The mixture is heated at 100 &lt; 0 &gt; C for 0.5 hour, dissolved and then resolidified. 114 g portions of the crude product are recrystallized from dimethylformamide to give 44.2 g of yellow crystals (mp: 227-228.5 캜).
[117] Example 11
[118] 1,4-dihydroquinoline-6-nitro-4-oxo-3-carbonitrile
[119] The 2-cyano-3- (4-nitro-phenyl-amino) acrylic acid ethyl ester 25.0g (95.8mmol) of slurry A 1.0L from Dow thumb 260 ℃ under N ₂ is heated for 12.5 hours. The cooled reaction is poured into 1.5 L of hexane. The product is collected, washed with hexane and hot ethanol, and then dried under vacuum. 18.7 g of a brown solid is obtained. Recrystallization from dimethylformamide / ethanol yields analytical samples: Mass spectrum (electrospray, m / e): M + H 216.
[120] Example 12
[121] 4-Chloro-6-nitro-3-quinolinecarbonitrile
[122] A mixture of 31.3 g (0.147 mol) of 6-nitro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile and 160 mL of phosphorus oxychloride is refluxed for 5.5 hours. The phosphorus oxychloride is removed in vacuo, the residue is poured into ice and neutralized with sodium bicarbonate. The product is collected, washed with water and then dried under vacuum (50 &lt; 0 &gt; C). 33.5 g of a tan solid are obtained: Mass spectrum (electrospray, m / e): M + H 234.
[123] Example 13
[124] 4 - [(3-bromophenyl) amino] -6-nitro-3-quinolinecarbonitrile
[125] A mixture of 17.0 g (73.1 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile and 15.1 g (87.7 mmol) of 3-bromoaniline in 425 mL of ethanol is refluxed for 5 hours. After adding saturated sodium bicarbonate, all volatiles are removed in vacuo. The residue is slurried with hexane, the product is collected and washed with hexane. The crude product is washed with water and then dried under vacuum (60 &lt; 0 &gt; C). 22.5 g of a yellow solid is obtained. Recrystallization from ethyl acetate gives an analytical sample (mp: 258-259 ° C).
[126] Example 14
[127] 6-Amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile
[128] Ethanol, 160mL of 4 - [(3-bromophenyl) amino] -6-nitro-3-quinoline hydrochloride 4.00g (10.8mmol) and for 1.3 hours a mixture of SnCl ₂ 12.2g (54.2mmol) under N ₂ Reflux. After cooling to 25 [deg.] C, ice water and sodium bicarbonate are added and the mixture is stirred for 2 hours. Extraction with chloroform, treatment with Darco followed by drying (magnesium sulphate) and removal of the solvent gave 3.9 g of brown crystals: Mass spectrum (electrospray, m / e): M + H 339 .
[129] Example 15
[130] N- [4- [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -2-butynamide
[131] Isobutyl chloroformate are added to (0.788g, 5.75mmol) and N- methylmorpholine (0.581g, 5.75mmol) under a N ₂ tetrahydrofuran 2-butyric acid ice naengaek 0.485g of 20mL (5.75mmol). After stirring for 10 minutes, a solution of 1.50 g (4.42 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile in 10 mL of tetrahydrofuran was added, Stir overnight. Then, 2 equivalents of the previously formed mixed anhydride is added. After 6 h, the reaction is poured into saturated sodium bicarbonate and brine. The product was collected, washed with hot ethyl acetate and dried under vacuum to give 0.638 g of a yellow solid (mp: 283-285 캜) (decomp.).
[132] Example 16
[133] N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] acetamide
[134] Amino-4 - [(3-bromophenyl) amino]] - 1,2,3,4-tetrahydroisoquinoline in 8 mL of methylene chloride and 6 mL of tetrahydrofuran under N ₂ was added triethylamine (0.359 g, 3.55 mmol) and acetyl chloride -3-quinolinecarbonitrile are added to 1.00 g (2.96 mmol) of ice cold solution. After stirring overnight at 25 [deg.] C, the volatiles are removed, the residue is slurried with water and then collected. Recrystallization from ethanol gave 0.543 g of a brown solid (mp: 258-261 占 폚) (decomp.).
[135] Example 17
[136] N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] butanamide
[137] Triethylamine (0.359g, 3.55mmol) and butyryl chloride (0.380g, 3.55mmol) under N ₂ in the 6-amino-tetrahydrofuran 12mL -4 - [(3- bromophenyl) amino)] - 3- Quinolinecarbonitrile are added to 1.00 g (2.96 mmol) of ice cold solution. After stirring overnight at 25 [deg.] C, the volatiles are removed, the residue is slurried with water and then collected. The residue is washed with boiling methanol and dried under vacuum to give 0.773 g of brown powder (mp: 276-276 占 폚) (decomp.).
[138] Example 18
[139] N- [4- [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -2-propenamide
[140] Triethylamine (0.359g, 3.55mmol) and acryloyl chloride (0.321g, 3.55mmol) in a 6 N 12mL of tetrahydrofuran under a _2-amino-4 - [(3-bromophenyl) amino)] - 3 -Quinolinecarbonitrile is added to 1.00 g (2.96 mmol) of ice cold solution. After stirring overnight at 25 [deg.] C, the volatiles are removed, the residue is slurried with water and then collected. Recrystallization from ethanol gave 0.580 g of a brown solid: Mass spectrum (electrospray, m / e): M + H 393,395.
[141] Example 19
[142] N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -2-chloroacetamide
[143] Triethylamine (0.359g, 3.55mmol) and chloroacetyl chloride (0.402g, 3.55mmol) under N ₂ in the 6-amino-tetrahydrofuran 12mL -4 - [(3- bromophenyl) amino)] - 3- Quinolinecarbonitrile are added to 1.00 g (2.96 mmol) of ice cold solution. After stirring overnight at 25 [deg.] C, the volatiles are removed, the residue is slurried with water and then collected. Recrystallization from methanol gave 0.540 g of a tan solid: Mass spectrum (electrospray, m / e): M + H 415,417.
[144] Example 20
[145] 4 - [(3,4-dibromophenyl) amino] -6-nitro-3-quinolinecarbonitrile
[146] A mixture of 6.20 g (26.6 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile and 8.00 g (31.9 mmol) of 3,4-dibromoaniline in 160 mL of ethanol is refluxed under N ₂ for 5 hours. Saturated sodium bicarbonate is added and the volatiles are then removed. The residue is slurried with hexane, collected, washed with hexane and water, and dried. The insoluble material is repeatedly extracted with boiling ethyl acetate, and the solution is then filtered through silica gel. Removal of the solvent gave 3.80 g of a green solid: mass spectrum (electrospray, m / e): M + H 449.
[147] Example 21
[148] 6-Amino-4 - [(3,4-dibromophenyl) amino] -3-quinolinecarbonitrile
[149] A mixture of 4.90 g (10.9 mmol) of 4 - [(3,4-dibromophenyl) amino] -6-nitro-3-quinolinecarbonitrile and 12.4 g (54.7 mmol) of SnCl ₂ dianhydride in 200 mL of ethanol was treated with N ₂ under reflux for 1.5 hours. After cooling to 25 &lt; 0 &gt; C, the reaction is diluted with ice water, neutralized with sodium bicarbonate and stirred for 2 hours. The solution is then extracted with chloroform, treated with Darco, dried (magnesium sulphate) and evaporated. After drying in vacuo (40 占 폚) 1.25 g of a brown solid were obtained: Mass spectrum (electrospray, m / e): M + H 417, 419, 421.
[150] Example 22
[151] N- [4 - [(3,4-dibromophenyl) amino] -3-cyano-6-quinolinyl]
[152] Isobutyl chloroformate (0.984 g, 7.18 mmol) and N-methylmorpholine (0.725 g, 7.18 mmol) are added to 0.604 g (7.18 mmol) of 2-butynoic acid in 25 ml of tetrahydrofuran under ice cooling. After 10 minutes, a solution of 1.20 g (2.87 mmol) of 6-amino-4 - [(3,4-dibromophenyl) amino] -3-quinolinecarbonitrile in 12 mL of tetrahydrofuran is added dropwise. After stirring at 25 &lt; 0 &gt; C overnight, the volatiles are removed, the residue is slurried with water and then filtered. The crude product was washed with boiling EtOAc and ethanol and dried under vacuum (50 DEG C) to give 0.651 g of a brown solid: Mass spectrum (electrospray, m / e): M + H 485.
[153] Example 23
[154] 6-Nitro-4 - [(3-trifluoromethylphenyl) amino] -3-quinolinecarbonitrile
[155] A mixture of 10.6 g (45.7 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile and 8.82 g (54.8 mmol) of 3- (trifluoromethyl) aniline in 270 mL of ethanol is refluxed under N ₂ for 5 hours . The reaction is diluted with ethanol, neutralized with saturated sodium bicarbonate and evaporated. The residue was slurried with hexane, collected, washed with hexane and water, and dried under vacuum (60 DEG C) to give 10.9 g of a yellow solid. 2.00 g of the sample is recrystallized from ethanol to give 1.20 g of a light yellow solid (mp: 260-261 ° C).
[156] Example 24
[157] 6-Amino-4- (3-trifluoromethylphenyl) amino] -3-quinolinecarbonitrile
[158] Ethanol 240mL of 6-nitro-4 - [(3-trifluoromethyl-phenyl) amino] quinoline-3-carbonitrile 6.00g (16.8mmol) and SnCl ₂ the slurry of the dianhydride, 18.9g (83.3mmol) under N ₂ 1 Lt; / RTI &gt; After cooling to 25 &lt; 0 &gt; C, the reaction is diluted with ice water, neutralized with sodium bicarbonate and stirred for 2 hours. The product is extracted with chloroform, treated with Darco, dried (magnesium sulphate) and evaporated. The residue was filtered through silica gel (10% methanol in chloroform), evaporated and dried under vacuum (40 캜) to give 4.87 g of a brown solid: Mass spectrum (electrospray, m / e): M + H 329.
[159] Example 25
[160] N- [4 - [(3-trifluoromethylphenyl) amino] -3-cyano-6-quinolinyl] -2-butynamide
[161] Isobutyl chloroformate (1.56g, 11.4mmol) and N- methylmorpholine (1.15g, 11.4mmol) was added under N ₂ to a tetrahydrofuran 2-butyric acid 0.961g (11.4mmol) in 40mL naengaek ice. After stirring for 10 minutes, a solution of 1.50 g (4.57 mmol) of 6-amino-4 - [(3-trifluoromethylphenyl) amino] -3-quinolinecarbonitrile in 12 mL of tetrahydrofuran is added dropwise. After stirring at 25 &lt; 0 &gt; C overnight, the volatiles are removed, the residue is slurried with water and then filtered. The crude product was washed three times with a small amount of hot ethyl acetate and dried under vacuum (45 캜) to give 0.831 g of a yellow solid: Mass spectrum (electrospray, m / e): M + H 395.
[162] Example 26
[163] 3-Carbethoxy-4-hydroxy-6,7-dimethoxyquinoline
[164] A mixture of 30.6 g of 4-aminoboratol and 43.2 g of diethyl ethoxymethylenemalonate is heated at 100 占 폚 for 2 hours and then at 165 占 폚 for 0.75 hours. The thus obtained intermediate is dissolved in 600 mL of diphenyl ether and the resulting solution is heated at reflux temperature for 2 hours, then cooled and diluted with hexane. The resulting solid was filtered, washed with hexane, washed with ether and then dried to give the title compound as a brown solid (mp: 275-285 [deg.] C).
[165] Example 27
[166] 3-Carbethoxy-4-chloro-6,7-dimethoxyquinoline
[167] A mixture of 28.8 g of 3-carveethoxy-4-hydroxy-6,7-dimethoxyquinoline and 16.6 mL of phosphorus oxychloride was stirred at 110 ° C for 30 minutes, cooled to 0 ° C, Lt; / RTI &gt; The resulting gray solid (mp: 147-150 ° C) is filtered, washed with water and ether, and dried.
[168] Example 28
[169] 4 - [(3-bromophenyl) amino] -6,7-dimethoxy-3-quinolinecarboxylic acid, ethyl ester
[170] A mixture of 14.8 g of 3-carboxyethoxy-4-chloro-6,7-dimethoxyquinoline, 9.46 g of 3-bromoaniline, 4.05 mL of pyridine and 150 mL of ethanol was refluxed for 30 minutes and evaporated to remove ethanol, Dissolve in dichloromethane-aqueous sodium bicarbonate. The organic layer is washed with water, dried and concentrated. The residue was recrystallized from ethanol to give a white solid (mp: 155- 158 [deg.] C).
[171] Example 29
[172] 4 - [(3-bromophenyl) amino] -6,7-dimethoxy-3-quinolinecarboxylic acid
[173] A mixture of 13 g of 4 - [(3-bromophenyl) amino] -3-quinolinecarboxylic acid, ethyl ester, 15 mL of 10 N sodium hydroxide and 300 mL of ethanol is refluxed for 2 hours. After evaporating most of the ethanol, the residue is diluted with water and oxidized to pH 7 using sodium dihydrogen phosphate. The resulting white solid (mp: 282-285 [deg.] C) is filtered, washed with water and then dried.
[174] Example 30
[175] 4 - [(3-bromophenyl) amino] -6,7-dimethoxy-3-quinolinecarboxamide
[176] 4.03 g of 4 - [(3-bromophenyl) amino] -6,7-dimethoxy-3-quinolinecarboxylic acid, 3.24 g of carbonyldiimidazole and 100 ml of dimethylformamide were heated at 55 DEG C for 30 minutes, Lt; / RTI &gt; and saturated with ammonia gas. After raising the temperature to 25 DEG C, the resulting solution is stirred for 45 minutes, heated at 50 DEG C and then evaporated to remove dimethylformamide. The residue is stirred with water and the resulting solid is filtered off, washed with water and dried. Recrystallization from acetone gave a gray solid (mp: 239-242 ° C).
[177] Example 31
[178] 4 - [(3-bromophenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile
[179] 3.18 mL of trifluoroacetic anhydride was added to a stirred mixture of 3.02 g of 4 - [(3-bromophenyl) amino] -6,7-dimethoxy-3-quinolinecarboxamide, 2.43 mL of pyridine and 22.5 mL of dichloromethane, Lt; 0 &gt; C for 3 minutes. The reaction mixture is warmed to 25 &lt; 0 &gt; C, stirred for 60 minutes and then concentrated. The residue is dissolved in 38 mL of methanol. The resulting solution is treated with 15 mL of 5N NaOH at 25 &lt; 0 &gt; C. After 5 minutes, the solution is oxidized to carbon dioxide and evaporated to remove methanol. The residue is partitioned with dichloromethane-water. The organic layer is washed with water, dried and evaporated to give a white solid. When recrystallized from ethyl acetate-hexane, the melting point is 224 to 228 占 폚.
[180] Example 32
[181] Ethyl 2-cyano-3- (3,4-dimethoxyphenylamino) acrylate
[182] A mixture of 7.66 g of 4-aminoboratol, 8.49 g of ethyl ethoxymethylene cyanoacetate and 20 mL of toluene is heated at 100 DEG C for 90 minutes. Evaporation of the toluene gives a solid (mp: 150-155 ° C).
[183] Example 33
[184] 1,4-dihydro-6,7-dimethoxy-4-oxo-3-quinolinecarbonitrile
[185] In which 2-cyano-3- (3,4-dimethoxy-phenylamino) acrylate 40g and Dow thumb ^R A and reflux a mixture of 1.2L for 10 hours, then cooled, diluted with hexane. The resulting solid (mp: 330-350 占 폚) (decomp.) Is filtered off, washed with hexane, washed with dichloromethane and dried.
[186] Example 34
[187] 4-Chloro-6, 7-dimethoxy-3-quinolinecarbonitrile
[188] A stirred mixture of 20 g of 1,4-dihydro-6,7-dimethoxy-4-oxo-3-quinolinecarbonitrile and 87 mL of phosphorus oxychloride is refluxed for 2 hours, cooled and then evaporated to remove volatiles . The residue is stirred with dichloromethane-water at 0 &lt; 0 &gt; C while adding solid sodium carbonate until the pH of the aqueous layer is 8. The organic layer is separated, washed with water, dried and concentrated. Recrystallization from dichloromethane afforded a solid (mp: 220-223 ° C).
[189] Example 35
[190] 4 - [(3-fluorophenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile
[191] A mixture of 1.00 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.89 g of 3-fluoroaniline, 0.32 mL of pyridine and 12 mL of ethoxyethanol was stirred under reflux for 4 hours. The mixture is cooled and partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer is washed with water, dried and concentrated. The residue is recrystallized from ethyl acetate to give a solid (mp: 226-230 占 폚).
[192] Example 36
[193] Methyl 2- (dimethylaminomethyleneamino) benzoate
[194] To 7.56 g of methyl anthranilate in 50 ml of dimethylformamide was added 5.6 ml of phosphorus oxychloride at 0 DEG C over 15 minutes. The mixture was heated at 55 &lt; 0 &gt; C for 45 min, cooled to 0 &lt; 0 &gt; C and then diluted with dichloromethane. The mixture is basified to pH 9 by slow addition of cold 1N NaOH at 0 &lt; 0 &gt; C. The dichloromethane layer is separated, washed with water, dried and concentrated to an oil.
[195] Example 37
[196] 1,4-dihydro-4-oxo-3-quinolinecarbonitrile
[197] A stirred mixture of 1.03 g of methyl 2- (dimethylaminomethyleneamino) benzoate, 0.54 g of sodium methoxide, 1.04 mL of acetonitrile and 10 mL of toluene is refluxed for 18 hours. The mixture is cooled, treated with water and then diluted with HCl to pH 3. The resulting solid is extracted with ethyl acetate. The extract is washed with water, dried and evaporated. The residue is recrystallized from ethanol to give a solid (mp: 290-300 C).
[198] Example 38
[199] 4- (cyclohexylamino) -6,7-dimethoxy-3-quinolinecarbonitrile
[200] A solution of 1.24 g (5 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 1.14 mL (0.99 g, 10 mmol) and 0.4 mL (0.39 g) of pyridine in 10 mL methylcellulose 0.0 &gt; 148 C &lt; / RTI &gt; for 3 hours. The reaction is poured into 25 mL of saturated aqueous sodium bicarbonate, and the resulting solid is filtered. The solid is dissolved in methylene chloride and the solution is passed through a Magnesol. The nucleic acid is added to the filtrate and the solution is evaporated on a hot plate until crystals are formed. Cooling to give 1.54 g (mp 193-195 DEG C) of 4- (cyclohexylamino) -6,7-dimethoxy-3-quinolinecarbonitrile: Mass spectrum (electrospray, m / e): M + H 312.1.
[201] Example 39
[202] 4 - [(3-bromophenyl) amino] -6,7-dihydroxy-3-quinolinecarbonitrile
[203] 5.11 g of 4 - [(3-bromophenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile and 30.74 g of pyridine hydrochloride are initially mixed and then heated at 207 占 폚 under nitrogen for 1 hour . Upon cooling, the reaction is treated with about 100 mL of water and the solid is filtered. The solid was warmed to methylcellulosorbate and washed with ether to give 3.00 g of 4 - [(3-bromophenyl) amino] -6,7-dihydroxy-3-quinolinecarbonitrile: Mass spectrum Electrospray, m / e): M + H 356,358.
[204] Example 40
[205] 8 - [(3-bromophenyl) amino] - [1,3] -dioxolo [4,5-g] quinoline-7-carbonitrile
[206] (6.09 mmol) of 4 - [(3-bromophenyl) amino] -6,7-dihydroxy-3-quinolinecarbonitrile in 0.5 mL of N, N-dimethylformamide, g, 9.14 mmol) and cesium carbonate (2.98 g, 9.14 mmol) was heated and then stirred in an oil bath at 111 DEG C for 2 hours. The reaction is poured into 75 mL of water, and then 50 mL of methylene chloride is extracted by dividing 4 times. The combined methylene chloride extracts are washed several times with water. The solution is converted to an oil in vacuo, which is then dissolved in ethyl acetate. The solution is washed with water and then repeatedly with brine. The solution was dried with anhydrous magnesium sulfate and changed to a solid in vacuo to give 8 - [(3-bromophenyl) amino] - [l, 3] -dioxolor4,5-gquinoline- 0.95 g of nitrile (mp: 201 to 205 ° C) is obtained. Mass spectrum (electrospray, m / e): M + H 368.1, 370.1.
[207] Example 41
[208] 4 - [(3-chlorophenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile
[209] A mixture of 0.5 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.51 g of 3-chloroaniline, 0.16 ml of pyridine and 6 ml of ethoxyethanol is stirred at reflux temperature for 6 hours under nitrogen. The mixture is cooled and partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer is washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate-hexane to give 0.37 g of 4 - [(3-chlorophenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile as a solid (mp: 214-217 ° C) do.
[210] Example 42
[211] 4 - [(3-Trifluoromethylphenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile
[212] A mixture of 1.24 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 1.61 g of 3-trifluoromethylaniline, 0.4 mL of pyridine and 15 mL of ethoxyethanol was stirred at reflux temperature for 5 hours under nitrogen . The mixture is cooled and partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer is washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate-hexane to give 1.34 g of 4 - [(3-trifluoromethylphenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile as a solid (mp: 190-193 ° C) &Lt; / RTI &gt;
[213] Example 43
[214] 4 - [(3,4-dimethoxyphenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile
[215] A mixture of 1.0 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 1.22 g of 3,4-dimethoxyaniline, 0.32 mL of pyridine and 12 mL of ethoxyethanol was stirred at reflux temperature for 5 hours under nitrogen . The mixture is cooled and partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer is washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate to give 0.96 g of 4 - [(3,4-dimethoxyphenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile as a solid (mp: 230-240 ° C) .
[216] Example 44
[217] 4 - [(methylphenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile
[218] A mixture of 0.86 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.86 g of N-methylaniline, 0.32 mL of pyridine and 12 mL of ethoxyethanol was stirred at reflux temperature for 24 hours under nitrogen. The mixture is cooled and partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer is washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate-hexane to give 0.54 g of 4 - [(methylphenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile as a solid (mp: 137-141 ° C).
[219] Example 45
[220] 4 - [(3-cyanophenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile
[221] A mixture of 0.5 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.47 g of 3-aminobenzonitrile, 0.16 ml of pyridine and 12 ml of ethoxyethanol is stirred at reflux temperature for 22 hours under nitrogen. The mixture is cooled and partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer is washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate-hexane to give 0.59 g of 4 - [(3-cyanophenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile as a solid (mp: 285-288 [ .
[222] Example 46
[223] 4 - [(4-fluorophenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile
[224] A mixture of 0.5 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.44 g of 4-fluoroaniline, 0.16 ml of pyridine and 6 ml of ethoxyethanol was stirred at reflux temperature for 4 hours under nitrogen. The mixture is cooled and partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer is washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate to give 0.59 g of 4 - [(4-fluorophenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile as a solid (mp: 282-285 캜) .
[225] Example 47
[226] 4 - [(3-bromophenyl) amino] -6,7-diethoxy-3-quinolinecarbonitrile
[227] 0.36 g of 4 - [(3-bromophenyl) amino] -6,7-dihydroxy-3-quinolinecarbonitrile, 0.32 mL of ethyl iodide and 0.55 g of potassium carbonate in 4 mL of dimethylsulfoxide was heated in an oil bath And stirred for 3 hours. Most of the solvent is removed under reduced pressure. The mixture is mixed with ethyl acetate and water. The organic layer is washed with water and then dried over magnesium sulfate. The solvent was removed and recrystallization from ethyl acetate gave 0.23 g of 4 - [(3-cyanophenyl) amino] -6,7-diethoxy-3-quinolinecarbonitrile (mp: 173-175 ° C) .
[228] Example 48
[229] 4 - [(3-hydroxymethyl) phenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile
[230] A mixture of 1.0 g of 4-chloro-6,7-dimethoxy-6,7-dimethoxy-3-quinolinecarbonitrile, 0.98 g of 3-aminobenzyl alcohol, 0.32 ml of pyridine and 12 ml of ethoxyethanol was stirred at reflux temperature Stir for 3 hours. The mixture is cooled and then partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer is washed with water, dried and evaporated. The residue was washed with hot methanol to obtain 1.16 g of 4 - [(3-hydroxymethyl) phenyl] amino] -6,7-dimethoxy-3-quinolinecarbonitrile as a solid (mp: do.
[231] Example 49
[232] 4- (3-Bromophenoxy) -6,7-dimethoxy-3-quinolinecarbonitrile
[233] A mixture of 0.16 g of 88% KOH and 1.73 g of 3-bromophenol is treated with 0.50 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile at 50 占 폚. The resulting mixture is heated to 170 &lt; 0 &gt; C for 30 minutes, cooled and then treated with 40 mL of 0.1 N NaOH at 0 &lt; 0 &gt; C. The resulting solid is filtered, washed with water and then dissolved in methylene chloride. The solution is treated with 0.5N NaOH and water, dried and concentrated. The resulting solid was recrystallized from methylene chloride-hexane to give 4- (3-bromophenoxy) -6,7-dimethoxy-3-quinolinecarbonitrile as a white solid (mp: 187-190 ° C) .
[234] Example 50
[235] 4 - [(4-bromophenyl) sulfanyl] -6,7-dimethoxy-3-quinolinecarbonitrile
[236] To 1.89 g of 4-bromothiophenol was added 0.16 g of 88% KOH at 25 DEG C under argon. The resulting mixture was heated at 85 占 폚 for 15 minutes, treated with 0.50 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, then heated at 140 占 폚 for 1 hour, Lt; / RTI &gt; The mixture is allowed to cool and then stirred at 0 &lt; 0 &gt; C with 40 mL of 0.1 N NaOH. The resulting solid is filtered, washed with water and then dissolved in methylene chloride. The solution is washed with 0.2N NaOH and water, dried and concentrated. The resulting solid was recrystallized from ethyl acetate to give 4 - [(3-bromophenoxy) sulfanyl] -6,7-dimethoxy-3-quinolinecarbonitrile as an off- white solid (mp: 173-175 ° C) .
[237] Example 51
[238] Amino] -3-cyano-6-quinolinyl] -3 (E) -chloro-2-propenamide
[239] And
[240] Example 52
[241] Amino] -3-cyano-6-quinolinyl] -3 (Z) -chloro-2-propenamide
[242] A mixture of 3 g (28.2 mmol) of cis-3-chloroacrylic acid and 3.3 mL (37.5 mmol) of oxalyl chloride in 30 mL of methylene chloride containing drop of dimethylformamide was stirred for 2.5 hours. The solvent is removed to give the acid chloride as a mixture of cis and trans isomers. (1.5 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile and 0.24 g (1.8 mmol) of N, N- diisopropylethylamine in 5 mL of tetrahydrofuran (1.7 mmol) of the 3-chloroacryloyl chloride isomer mixture was added over 4 minutes with stirring at 0 &lt; 0 &gt; C under nitrogen. After 40 min at 0 &lt; 0 &gt; C, the solution is diluted with ether. The solid is collected and then dissolved in a mixture of tetrahydrofuran and ethyl acetate. The mixture is washed with brine and dried over magnesium sulfate. The solvent is removed. The residue is chromatographed on silica gel, eluting with chloroform-ethyl acetate. Two products are obtained. The less polar product is N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -3 (E) -chloro-2-propenamide: mass spectrum Electrospray, m / e): M + H 424.9, 427.0. The more polar product is N- [4- [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -3 (Z) -chloro-2-propenamide: mass spectrum Electrospray, m / e): M + H 425.0, 427.0.
[243] Example 53
[244] N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -2-methyl-
[245] To a solution of 0.5 g (1.48 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile and 0.194 g (1.92 mmol) of triethylamine in 6 mL of tetrahydrofuran, 0.21 g (1.92 mmol) of monochloride are added over 10 minutes with stirring at 0 &lt; 0 &gt; C under nitrogen. The solution is stirred at room temperature overnight. The mixture is poured into water. The solid is collected and dried in air. The solid was washed with boiling ethyl acetate and then dried in air to give N- [4- [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] (Electrospray, m / e): M &lt; + &gt; H 407,409.
[246] Example 54
[247] N- [4 - [(3,4-dibromophenyl) amino] -3-cyano-6-quinolinyl] -2-propenamide
[248] To a solution of 0.75 g (1.79 mmol) of triethylamine in 0.22 g (2.15 mmol) of 6-amino-4 - [(3,4-dibromophenyl) amino] -3-quinolinecarbonitrile in 10 mL of tetrahydrofuran was added acryloyl 0.195 g (2.15 mmol) of chloride are added dropwise. After stirring overnight at 25 &lt; 0 &gt; C, the volatiles are removed, the residue is slurried with water and the solid is collected. The crude product was washed with boiling ethyl acetate and dried under vacuum (50 캜) to give 0.609 g of a brown solid: High resolution mass spectrum (m / e): M + H 470.9457.
[249] Example 55
[250] N- [4 - [(5-bromo-3-pyridinyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile
[251] (1 mmol) of 3-cyano-4-chloro-6,7-dimethoxyquinoline in 5 mL of 2-methoxyethanol, 346 mg (2 mmol) of 3-amino-5-bromopyridine and 20 mg of p-toluenesulfonic acid monohydrate (About 0.1 mmol) is stirred in an oil bath at 153 &lt; 0 &gt; C for 7 hours and then refluxed. After cooling to room temperature overnight, the solid was filtered, washed with ethanol and then washed with ether to give N- [4 [(5-bromo-3-pyridine) amino] -6,7 (Electrospray, m / e): M + H 384.9, 386.8. &Lt; RTI ID = 0.0 &gt;
[252] Example 56
[253] 4 - [(3-bromophenyl) amino] -6,7-bis (methoxymethoxy) -3-quinolinecarbonitrile
[254] A mixture of 0.36 g of 4 - [(3-bromophenyl) amino] -6,7-dihydroxy-3-quinolinecarbonitrile, 0.30 mL of 2-chloromethyl methyl ether and 0.55 g of potassium carbonate in 4 mL of dimethylformamide Stir at 0 ° C for 6 hours. Most of the solvent is removed under reduced pressure. The mixture is mixed with ethyl acetate and water and then the pH is adjusted to 8 using dilute hydrochloric acid. The organic layer is washed with water and then dried over magnesium sulfate. Removal of the solvent gave 4 - [(3-bromophenyl) amino] -6,7-bis (methoxymethoxy) -3-quinolinecarbonitrile which was purified by column chromatography on silica gel: mass spectrum (Electrospray, m / e): M + H 356,358.
[255] Example 57
[256] N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-hydroxy-
[257] Isobutyl chloroformate (0.214g, 1.57mmol) and N- methylmorpholine (0.190g, 1.88mmol) under a N ₂ 4- in 15mL of tetrahydrofuran (t- butyl-dimethyl-silanyloxy) -2- 0.336 g (1.57 mmol) of butanoic acid was added to the ice cold solution. After stirring for 30 minutes, the mixture was transferred to an additional funnel which was capped with glass wool and then a solution of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile Is added dropwise to a solution of 0.4 g (1.18 mmol) of The mixture is stirred at 25 &lt; 0 &gt; C for 1 hour. The reaction solution is poured into ethyl acetate and washed with saturated sodium bicarbonate and brine. The product was collected and purified by flash column chromatography (60% ethyl acetate in hexanes) to give N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl ] -4 (t-butyl-dimethyl-silanyloxy) -2-butyne amide, 0.220 g (35%); ESMS m / z 535.1 (M + H &lt; ⁺ & gt ^; ); mp ° C (decomposition).
[258] Butyl-dimethyl-silanyloxy) -2-butyne amide (0.120 g, 0.20 mmol) was added to a solution of N- [4- [ 0.224 mmol) was dissolved in 25 mL of a solution (acetic acid: tetrahydrofuran: water = 3: 1: 1) and stirred overnight at 25 ° C. The reaction is poured into ethyl acetate and washed with saturated sodium bicarbonate and brine. The product was collected, washed with ethyl acetate and dried under vacuum to give 0.085 g (90%) of a yellow solid (mp 253-254 占 폚) (decomp.); ESMS m / z 421.2 (M + H ^& lt ^{; +} & gt ^; ).
[259] Example 58
[260] N- [4- [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-morpholino-2-butynamide
[261] Isobutyl chloroformate 4-morpholino-2-butyric acid 0.250g (1.48mmol) of (0.161g, 1.18mmol) and N- methylmorpholine (0.150g, 1.48mmol) in tetrahydrofuran 10mL under N ₂ Add to ice cold. After stirring for 30 minutes, a solution of 0.250 g (0.74 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile in 8 mL of pyridine was added, Lt; / RTI &gt; The reaction is quenched with ice water and then poured into saturated sodium bicarbonate and brine. The product was collected, washed with ethyl acetate and dried under vacuum to give 0.096 g (27%) of a yellow solid (mp 112-115 ° C) (decomposition); ESMS m / z 490.1 (M + H ^& lt ^{; +} & gt ^; ).
[262] Example 59
[263] N- [4- [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-dimethylamino-
[264] Isobutyl chloroformate (0.260g, 1.91mmol) and N- methylmorpholine (0.594g, 5.88mmol) in tetrahydrofuran 4-dimethylamino-2-butyric acid 0.370g (2.94mmol) in 50mL under ice-N ₂ Add to cold. After stirring for 30 minutes, a solution of 0.500 g (1.47 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile in 10 mL of pyridine was added, Lt; / RTI &gt; The reaction is quenched with ice water and then poured into saturated sodium bicarbonate and brine. The product was collected, washed with ethyl acetate and dried under vacuum to give 0.144 g (21%) of a yellow solid (mp 114-118 ° C) (decomp.); ESMS m / z 448.0 (M + H ^& lt ^{; +} & gt ^; ).
[265] Example 60
[266] N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-methoxy-
[267] Isobutyl chloroformate (0.410g, 3.0mmol) and N- methylmorpholine (0.910g, 9.0mmol) in tetrahydrofuran 4-methoxy-2-butyric acid 0.680g (6.0mmol) in 20mL under ice-N ₂ Add to cold. After stirring for 30 minutes, a solution of 0.500 g (1.47 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile in 10 mL of pyridine was added, Lt; / RTI &gt; The reaction is quenched with ice water and then poured into saturated sodium bicarbonate and brine. The product was collected, washed with ethyl acetate and dried under vacuum to give 0.200 g (35%) of a yellow solid (mp 198-202 ° C) (decomp.); ESMS m / z 435.1 (M + H ^& lt ^{; +} & gt ^; ).
[268] Example 61
[269] 4- (3-Bromophenylmethylamino) -6,7-diethoxy-3-quinolinecarbonitrile
[270] (0.69 g, 2.5 mmol), 3-bromobenzylamine (0.78 g, 3.5 mmol) and diisopropylethylamine (1.05 mL, 6.0 mmol) were added to a solution of 4-chloro-6,7-diethoxy- And 7.5 mL ethoxyethanol is refluxed for 4 hours, cooled and then stirred with a mixture of hexane and water containing 0.4 g of potassium carbonate for 3 hours. The resulting solid is filtered, washed with water and dried. Recrystallization from acetone-hexane gave 0.73 g of an off-white solid (mp: 156-159 DEG C).
[271] Example 62
[272] 4- (3-phenylmethylamino) -6,7-diethoxy-3-quinolinecarbonitrile
[273] Chloro-6,7-diethoxy-3-quinolinecarbonitrile is reacted with benzylamine in the manner of Example 61 to give the title compound as an off-white solid (mp: 150-153 占 폚).
[274] Example 63
[275] 4- (3,4-dimethoxyphenylmethylamino) -6,7-diethoxy-3-quinolinecarbonitrile
[276] 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile was reacted with 3,4-dimethoxybenzylamine in the manner of Example 61 to obtain the title compound as a tan solid (mp: 200-204 ° C) &Lt; / RTI &gt;
[277] Example 64
[278] 4- (3,4-Dichlorophenylmethylamino) -6,7-diethoxy-3-quinolinecarbonitrile
[279] Chloro-6,7-diethoxy-3-quinolinecarbonitrile was reacted with 3,4-dichlorobenzylamine in the manner of Example 61 to give the title compound as a tan solid (mp: 163-165 占 폚) do.
[280] Example 65
[281] Methoxy-but-2-enoic acid [4- (3-bromo-phenylamino) -3- cyano-quinolin-
[282] To a solution of 1.0 g (2.95 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile and 0.57 g (4.42 mmol) of diisopropylethylamine was added 4-methoxycrotonyl chloride 0.43 g (3.24 mmol) at 0 &lt; 0 &gt; C with stirring. After 1.5 h at 0 C, the mixture is poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution is dried over magnesium sulfate and the solvent is removed. The residue was recrystallized from 1-butanol to give 4-methoxy-but-2-enoic acid [4- (3-bromo-phenylamino) -3- cyano-quinolin- Amide 1.3 g: Mass spectrum (electrospray, m / e): M + H 436.4, 438.9.
[283] Example 66
[284] 4- (3-Chloro-propoxy) -5-methoxy-benzoic acid methyl ester
[285] (411.7 mmol) of 3-chloropropyl p-toluene sulfonate, 4-hydroxy-5-methoxy-benzoic acid methyl ester, 75.7 g (547.5 mmol) A mixture of 1.66 g (4.1 mmol) of caprylammonium chloride is rapidly stirred under reflux for 18 hours. The mixture is filtered, the solvent is removed, and 106 g of the title compound are obtained after recrystallization from a chloroform-hexane mixture.
[286] Example 67
[287] 4- (2-Chloro-ethoxy) -5-methoxy-benzoic acid methyl ester
[288] Using the same method as above, 77 g of 4-hydroxy-5-methoxy-benzoic acid methyl ester, 99.2 g of 2-chloroethyl p-toluenesulfonate, 77.7 g of potassium carbonate and 1.7 g of methyl-tricapryl ammonium chloride (4.1 mmol) was converted to 91.6 g of the title compound: Mass spectrum (electrospray, m / e): M + H 245.0.
[289] Example 68
[290] 4- (3-Chloro-propoxy) -5-methoxy-2-nitro-benzoic acid methyl ester
[291] 100 mL of 70% nitric acid is added dropwise to a solution of 100 g (386.5 mmol) of 4- (3-chloro-propoxy) -5-methoxy-benzoic acid methyl ester in 300 mL of acetic acid. The mixture is heated to 50 &lt; 0 &gt; C for 1 hour and then poured into ice water. The mixture is extracted with chloroform. The organic solution is washed with dilute sodium hydroxide and then dried over magnesium sulfate. The solvent is removed. The ether added to the mixture is stirred until a solid precipitates. The solid was collected by filtration to give 98 g of 4- (3-chloro-propoxy) -5-methoxy-2-nitro-benzoic acid methyl ester as white crystals: Mass spectrum (electrospray, m / e): M + H 303.8; 2M + NH ₄ 623.9.
[292] Example 69
[293] 4- (2-Chloro-ethoxy) -5-methoxy-2-nitro-benzoic acid methyl ester
[294] 85 g of 4- (2-chloro-ethoxy) -5-methoxy-benzoic acid methyl ester was nitrated using the same method as above to give 72 g of the title compound: Mass spectrum (electrospray, m / e) : 2M + NH ₄ 595.89.
[295] Example 70
[296] 2-Amino-4- (3-chloro-propoxy) -5-methoxy-benzoic acid methyl ester
[297] A mixture of 91 g (299.6 mmol) of 4- (3-chloro-propoxy) -5-methoxy-2-nitro-benzoic acid methyl ester and 55.2 g (988.8 mmol) of iron was treated with 60.1 g of ammonium chloride, 500 mL of water and 1300 mL Lt; / RTI &gt; under mechanical stirring at reflux for 5.5 hours. The mixture is concentrated and then mixed with ethyl acetate. The organic solution is washed with water and saturated sodium bicarbonate. The solution is dried over magnesium sulfate and then filtered through a short silica gel column. After removal of the solvent, the residue is mixed with 300 mL of ether-hexane (2: 1). After standing, 73.9 g of the title compound were obtained as a pink solid: mass spectrum (electrospray, m / e): 2M-HCl + H 511.0; M + H 273.8.
[298] Example 71
[299] 2-Amino-4- (2-chloro-ethoxy) -5-methoxy-benzoic acid methyl ester
[300] A mixture of 68.2 g (235.4 mmol) of 4- (2-chloro-ethoxy) -5-methoxy-2-nitro-benzoic acid methyl ester and 52.6 g (941.8 mmol) of iron was treated with 62.9 g of ammonium chloride, 393 mL of water, Lt; / RTI &gt; for 15 hours under reflux. The mixture is concentrated and then mixed with ethyl acetate. The organic solution is washed with water and saturated sodium bicarbonate. The solution is dried over magnesium sulfate and then filtered through a short silica gel column. The solution is concentrated to 200 mL and then diluted with 250 mL of hot hexane. After standing, 47.7 g of the title compound are obtained as a solid: mass spectrum (electrospray, m / e): M + H 259.8.
[301] Example 72
[302] 7- (2-Chloro-ethoxy) -4-hydroxy-6-methoxy-quinoline-
[303] A mixture of 25 g (96.3 mmol) of 2-amino-4- (2-chloro-ethoxy) -5-methoxy-benzoic acid methyl ester and 17.2 g (144.4 mmol) of dimethylformamide dimethylacetal was heated under reflux for 1.5 hours . Excess reagent is removed under reduced pressure to leave 30.3 g of the residue dissolved in 350 mL of tetrahydrofuran. To the separating flask, 8.3 g (202.1 mmol) of acetonitrile is added dropwise over 40 minutes to a solution of 80.9 mL of 2.5 M n-butyllithium in hexane in 300 mL of tetrahydrofuran. After 30 minutes, the amidine solution is added dropwise at -78 &lt; 0 &gt; C over 45 minutes. After 1 hour, 27.5 mL of acetic acid is added and the mixture is allowed to warm to room temperature. After removing the solvent, water is added. The solid is collected by filtration and washed with water and ether. After drying in vacuo, 18.5 g of the title compound are obtained as a tan brown powder: Mass spectrum (electrospray, m / e): M + H 278.8.
[304] Example 73
[305] 7- (3-Chloro-propoxy) -4-hydroxy-6-methoxy-quinoline-
[306] Using the above method, 3.7 g of the corresponding amidine, 1.58 g of acetonitrile and 15.35 mL of n-butyllithium solution were used to yield 3.7 g of the title compound as a tan brown powder: Mass spectrum (electrospray, m / e) : M @ + H 292.8; 2M + H 584.2.
[307] Example 74
[308] 7- (3-Chloro-propoxy) -4-chloro-6-methoxy-quinoline-
[309] A mixture of 3.5 g (12 mmol) of 7- (3-chloro-propoxy) -4-hydroxy-6-methoxy-quinolin-3-carbonitrile and 28 mL of phosphorus oxychloride is refluxed for 1.5 h. Excess reagent is removed under reduced pressure. The residue is mixed with cold dilute sodium hydroxide solution and ethyl acetate. The mixture is extracted by mixing ethyl acetate and tetrahydrofuran. The combined extracts are washed with saturated sodium bicarbonate, dried over magnesium sulfate and filtered through a short silica gel column. Removal of the solvent gave 3.2 g of the title compound, which was used without further purification as a pink solid.
[310] Example 75
[311] 7- (3-Chloro-ethoxy) -4-chloro-6-methoxy-quinoline-
[312] (28.7 mmol) of 7- (3-chloro-ethoxy) -4-hydroxy-6-methoxy-quinoline-3-carbonitrile in 80 mL of methylene chloride containing 0.26 g of dimethylformamide and 18.2 g (143.5 mmol) in dichloromethane (5 ml) was stirred under reflux for 2.5 hours. The solvent is removed. The residue is mixed with cold dilute sodium hydroxide and extracted several times with ethyl acetate and tetrahydrobutane. The combined extracts are dried over magnesium sulfate and the solution is passed through a short silica gel column. The solvent was removed to give 6.0 g of the title compound, which was used without further purification as an off-white solid.
[313] Example 76
[314] Fluoro-phenylamino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile
[315] (9.96 mmol) of 7- (3-chloro-propoxy) -4-chloro-6-methoxy-quinoline- 1.6 g (10.96 mmol) and 1.2 g (10 mmol) of pyridine hydrochloride is stirred under reflux for 1.5 hours. The mixture is poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution is dried and then the solvent is removed. Purification of the residue on silica gel, eluting with a chloroform-ether mixture, gave 2.88 g of the title compound as off-white solid powder. Mass spectrum (electrospray, m / e): M + H 419.7.
[316] Example 77
[317] 4- (3-Hydroxy-4-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile
[318] Using this method, 3 g of 7- (2-chloro-ethoxy) -4-chloro-6-methoxy-quinolin-3-carbonitrile, 1.37 g of 3-hydroxy- Starting with 1.2 g, 2.6 g of the title compound was obtained as a crystalline solid: mass spectrum (electrospray, m / e): M + H 383.9.
[319] Example 78
[320] Chloro-propoxy)) - 6-methoxy-quinoline-3-carbonitrile &lt; / RTI &gt;
[321] Using this method, 3 g of 7- (3-chloro-propoxy) -4-chloro-6-methoxy-quinoline-3-carbonitrile in 30 mL of 2-ethoxyethanol, 2.35 g of 5-hydroxy-aniline methylcarbonate and 1.1 g of pyridine hydrochloride were stirred to give 1.7 g of the title compound as a crystalline solid: Mass spectrum (electrospray, m / e): M + H 435.8, 437.8 .
[322] Example 79
[323] Chloro-2-fluoro-5-hydroxy-phenylamino) -7- (2- chloro-ethoxy)) - 6-methoxy-quinoline-
[324] Using this method, 3 g of 7- (2-chloro-ethoxy) -4-chloro-6-methoxy-quinoline- 2.46 g of methyl carbonate of 5-hydroxy-aniline and 1.18 g of pyridine hydrochloride were stirred to give 2.2 g of the title compound as a tan solid: Mass spectrum (electrospray, m / e): M + H 421.9.
[325] Example 80
[326] Chloro-2-fluoro-phenylamino) -7- (3-dimethylamino-propoxy) -6-methoxy-quinoline-
[327] To a solution of 4-chloro-2-fluoro-phenylamino) -7- (3-chloro-propoxy) -6-methoxy- quinolin-3-carbonitrile (17.85 mL) in 2M dimethylamine in tetrahydrofuran 2.38 mmol) and 0.07 g of sodium iodide is placed in a sealed tube and heated at 125 [deg.] C for 3.5 hours. After removal of the solvent, the residue is mixed with warm ethyl acetate and saturated sodium bicarbonate. The organic layer is separated and dried with magnesium sulfate. The solvent is removed and ether is added. With one single settling, crystals precipitated to give 0.93 g of the title compound as a white solid: Mass spectrum (electrospray, m / e): M + H 428.9.
[328] Example 81
[329] Chloro-2-fluoro-phenylamino) -6-methoxy-7- (3-morpholin-4- yl-propoxy) -quinoline-
[330] To a solution of 1 g (2.38 mmol) of 4- (4-chloro-2-fluoro-phenylamino) -7- (3-chloro-propoxy) -6-methoxy- quinoline- A mixture of 3.1 g (35.7 mL) of morpholine and 0.07 g of sodium iodide is refluxed for 7 hours. After removal of the solvent, the residue is mixed with warm ethyl acetate and saturated sodium bicarbonate. The organic layer is separated and dried with magnesium sulfate. The solvent is removed and then ether-hexane is added. With one single settling, crystals precipitated to give 1.1 g of the title compound as an off-white solid: Mass spectrum (electrospray, m / e): M + H 470.9.
[331] Example 82
[332] 4- (3-Hydroxy-4-methyl-phenylamino) -6-methoxy-quinoline-3-carbonitrile
[333] 4-methyl-phenylamino) -6-methoxy-quinoline-3-carbonitrile in 19.5 mL of 2M dimethylamine in tetrahydrofuran was added dropwise a solution of 7- (2-chloro-ethoxy) -4- 2.38 mmol) and 0.078 g of sodium iodide is placed in a sealed tube and heated at 125 &lt; 0 &gt; C for 14 hours. After removal of the solvent, the residue is mixed with warm ethyl acetate and saturated sodium bicarbonate. The organic layer is separated and dried with magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate-methanol-triethylamine (70: 30: 2.5) to give 0.89 g of the title compound as a pale yellow solid: Mass spectrum (electrospray, m / e): M + H 393.0; (M + 2H) &lt; ⁺ &gt;
[334] Example 83
[335] Methyl-phenylamino) -6-methoxy-7- (2-morpholin-4-yl-ethoxy) -quinoline-3-carbonitrile
[336] (2.38 mmol) of 7- (2-chloro-ethoxy) -4- (3-hydroxy-4-methyl- phenylamino) -6-methoxy-quinoline- 3.4 g (39 mmol) of morpholine and 0.08 g of sodium iodide is refluxed for 34 hours. After removal of the solvent, the residue is mixed with warm ethyl acetate and saturated sodium bicarbonate. The organic layer is separated and dried with magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel, eluting with ethyl acetate-methanol-triethylamine (70: 30: 2.5) to give 1.05 g of the title compound as a pale orange solid: mass spectrum , &lt; / RTI &gt; m / e): M + H 435.0; (M + 2H) &lt; ⁺ &gt;
[337] Example 84
[338] Chloro-2-fluoro-5-hydroxy-phenylamino) -7- (3-dimethylamino-propoxy) -6-methoxy-quinoline-
[339] Chloro-2-fluoro-5-hydroxy-phenylamino) -7- (3-chloro-propoxy) -6-methoxy-quinolin- (1.83 mmol) of carbonitrile and 0.055 g of sodium iodide is placed in a sealed tube and then heated at 125 [deg.] C for 2.5 hours. The solvent is removed and the residue is mixed with warm ethyl acetate and saturated sodium bicarbonate. The organic layer is separated and dried with magnesium sulfate. The solvent was removed and the residue was treated with ethyl acetate-ether to precipitate a solid to give 0.51 g of the title compound as off-white solid: Mass spectrum (electrospray, m / e): M + H 445.0; (M + 2H) &lt; ⁺ &gt;
[340] Example 85
[341] Chloro-2-fluoro-5-hydroxy-phenylamino) -6-methoxy- 7- (3-morpholin-4- yl- propoxy) -quinoline-
[342] (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile 0.8 g (1.83 mmol), morpholine (2.4 g, 27.5 mmol) and sodium iodide (0.11 g) is refluxed for 7 hours. After removal of the solvent, the residue is mixed with warm ethyl acetate and saturated sodium bicarbonate. The organic layer is separated and dried with magnesium sulfate. The solvent was removed and the residue was recrystallized from ethyl acetate-carbon tetrachloride to give 0.63 g of the title compound as a pale yellow-brown solid: Mass spectrum (electrospray, m / e): M + H 487.0; (M + 2H) &lt; ⁺ &gt; 243.9.
[343] Example 86
[344] Chloro-2-fluoro-5-hydroxy-phenylamino) -7- (2-dimethylamino-ethoxy) -6-methoxy-quinoline-
[345] Chloro-2-fluoro-5-hydroxy-phenylamino) -7- (2-chloro-ethoxy) -6-methoxy-quinolin-3 in 16.1 mL of 2M dimethylamine in tetrahydrofuran (1.83 mmol) of carbonitrile and 0.11 g of sodium iodide is placed in a sealed tube and then heated at 135 占 폚 for 14 hours. After removal of the solvent, the residue is mixed with warm ethyl acetate and saturated sodium bicarbonate. The organic layer is separated and dried with magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with acetate-methanol-triethylamine (60: 40: 3) to give 0.41 g of the title compound as a tan solid: mass spectrum (electrospray, m / e): M + H 430.9; (M + 2H) &lt; ⁺ &gt; 216.0.
[346] Example 87
[347] Chloro-2-fluoro-5-hydroxy-phenylamino) -6-methoxy- 7- (2-morpholin-4-yl-ethoxy) -quinoline-
[348] (2-chloro-ethoxy) -6-methoxy-quinoline-3-carbonitrile 0.8 g (1.83 mmol) of morpholine, 2.4 g (27.5 mmol) of morpholine and 0.11 g of sodium iodide is heated in a sealed tube and then heated at 135 DEG C for 12 hours. After removal of the solvent, the residue is mixed with warm ethyl acetate and saturated sodium bicarbonate. The organic layer is separated and dried with magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with acetate-methanol-triethylamine (70: 30: 1) to give 0.43 g of the title compound as a tan solid: mass spectrum (electrospray, m / e): M + H 470.0; (M + 2H) &lt; ⁺ &gt; 237.0.
[349] Example 88
[350] N- [3-cyano-4- (3-fluorophenylamino) quinolin-6-yl]
[351] A solution of 1.00 g (3.60 mmol) of 6-amino-4- (3-fluorophenylamino) quinoline-3-carbonitrile in 12 mL of THF is quenched on ice under N ₂ . Triethylamine (0.436 g, 4.32 mmol) was added, and 0.393 g (4.32 mmol) of anilyloyl chloride was added and the reaction was stirred overnight at 25 <0> C. The solvent is removed, the residue is slurried with water and then filtered. The crude product is washed with water, dried, then washed with hot ethyl acetate and dried under vacuum (50 &lt; 0 &gt; C). Thus, 0.862 g of N- [3-cyano-4- (3-fluorophenylamino) quinolin-6-yl] acrylamide was obtained as a brown solid: Mass spectrum (electrospray, m / e): M + H 333.1.
[352] Example 89
[353] 6,7-Dimethoxy-4- (3-nitrophenylamino) quinoline-3-carbonitrile
[354] A solution of 0.500 g (2.00 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile and 0.332 g (2.41 mmol) of 3-nitryl aniline in 6 mL of methyl cellosolve is refluxed under N ₂ for 8 hours. Methanol is added, saturated NaHCO ₃ (pH 8) is added, and the volatiles are removed. The residue is slurried with water, collected by filtration and dried. Recrystallization from ethanol gave 0.480 g of 6,7-dimethoxy-4- (3-nitrophenylamino) quinoline-3-carbonitrile as yellow crystals: Mass spectrum (electrospray, m / e): M + H 351.0.
[355] Example 90
[356] 4- (3-Bromophenylamino) -6-ethoxy-7-methoxyquinoline-3-carbonitrile
[357] A mixture of 1.00 g (3.82 mmol) of 4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile and 0.788 g (4.58 mmol) of 3-bromoaniline in 20 mL of ethanol was treated under N ₂ for 7 h Reflux. Saturated NaHCO ₃ is added, the volatiles are removed and the residue is azeotropically mixed with ethanol. The crude product is slurried with hexane, filtered, washed with water and dried. Recrystallization from ethanol gave 1.31 g of 4- (3-bromophenylamino) -6-ethoxy-7-methoxyquinoline-3-carbonitrile as yellowish brown crystals: mass spectrum (electrospray, m / e ): &Lt; / RTI &gt; M + H 397.7, 399.8.
[358] Example 91
[359] 4-Chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile
[360] A mixture of 7.95 g (32.6 mmol) of 6-ethoxy-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile and 50 mL of phosphorus oxychloride is refluxed for 3 hours and 40 minutes. The phosphorus oxychloride is removed in vacuo and the residue is slurried with ice water. Solid NaHCO ₃ is added (pH 8) and the product is collected by filtration, then washed well with water and dried under vacuum (40 ° C). 7.75 g of 4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile as a tan solid: mass spectrum (electrospray, m / e): M + H 262.8, 264.8.
[361] Example 92
[362] 6-Ethoxy-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile
[363] A solution of 10.2 g (45.3 mmol) of methyl 2-amino-5-ethoxy-4-methoxybenzoate and 10.8 g (90.7 mmol) of dimethylformamide dimethylacetal in 50 mL of dimethylformamide is refluxed for 3 hours. The volatiles are removed, the residue is azeotropically mixed with toluene and then dried under vacuum to give formamidine as a purple syrup. N-Butyl lithium (100 mmol) in hexane is diluted with 60 mL of tetrahydrofuran at -78 &lt; 0 &gt; C. A solution of 4.18 g (102 mmol) of acetonitrile in 80 mL of tetrahydrofuran is added over 15 minutes and the solution is then stirred for 20 minutes. The crude formamidine is dissolved in 80 mL of tetrahydrofuran, and then the solution is added dropwise to the cooling solution over 0.5 hour. After stirring for 2 h, the reaction is quenched at -78 [deg.] C with 13 mL of acetic acid. After warming to room temperature, the volatiles are removed in vacuo. The residue is slurried with water, the crude product is collected by filtration, washed well with water, and dried. The material was then washed with chloroform and dried to give 7.95 g of 6-ethoxy-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile as yellow crystals: Mass spectrum (Electrospray, m / e): MH 243.2.
[364] Example 93
[365] Methyl 2-amino-5-ethoxy-4-methoxybenzoate
[366] A mixture of 17.0 g (66.7 mmol) of methyl 5-ethoxy-4-methoxy-2-nitrobenzoate, 13.1 g (233 mmol) of iron powder and 17.7 g (334 mmol) of ammonium chloride in 95 mL of water and 245 mL of methanol was stirred for 4.5 h Reflux. 13.1 g of iron is further added, and the mixture is refluxed for 2.5 hours. Then, 13.1 g of iron is further added, 17.7 g of ammonium chloride is added, and the mixture is refluxed continuously for 12 hours. The reaction is filtered through Celite and the methanol is removed from the filtrate. The filtrate is extracted with chloroform, the extract is treated with Dharco and dried under vacuum (50 &lt; 0 &gt; C). 11.0 g of methyl 2-amino-5-ethoxy-4-methoxybenzoate as yellowish brown crystals were obtained: Mass spectrum (electrospray, m / e): M + H 225.9.
[367] Example 94
[368] Methyl 5-ethoxy-4-methoxy-2-nitrobenzoate
[369] A mixture of 15.0 g (74.1 mmol) of methyl 3-ethoxy-4-methoxybenzoate in 45 mL of acetic acid is treated with 15 mL of concentrated nitric acid over 12 minutes. The reaction is held at 55 占 폚 for 45 minutes, cooled to 25 占 폚 and poured into ice water. The product is extracted with methylene chloride and the extract is washed with water and dilute sodium hydroxide, then dried and evaporated. 17.8 g of methyl 5-ethoxy-4-methoxy-2-nitrobenzoate as yellow crystals: mass spectrum (electrospray, m / e): M + H 256.0.
[370] Example 95
[371] Methyl-3-ethoxy-4-methoxybenzoate
[372] A mixture of 24.3 g (134 mmol) of methyl 3-hydroxy-4-methoxybenzoate, 36.8 g (267 mmol) of anhydrous potassium carbonate and 31.4 g (201 mmol) of ethyl iodide in 500 ml of dimethylformamide is stirred at 100 ° C. for 5.5 hours . Additional amounts of ethyl iodide (31.4 g) and potassium carbonate (18.4 g) were added and then heated for 2 hours or more. The reaction is filtered and the volatiles are removed from the filtrate under vacuum. The residue is slurried with water, filtered, and the product washed with water is collected and dried. Recrystallization from heptane gave 1.56 g of methyl 3-ethoxy-4-methoxybenzoate as white crystals: mass spectrum (electrospray, m / e): M + H 210.9.
[373] Example 96
[374] Methyl 3-hydroxy-4-methoxybenzoate
[375] A solution of 30.8 g (183 mmol) of 3-hydroxy-4-methoxybenzoic acid and 6 mL of concentrated sulfuric acid in 600 mL of methanol is refluxed overnight. After removing most of the solvent, pour the remaining solution into 600 mL of water containing 25 g of sodium bicarbonate. The product is extracted with ether, treated with Darco, dried and evaporated. 31.8 g of methyl 3-hydroxy-4-methoxybenzoate are obtained as pale yellow crystals.
[376] Example 97
[377] Ethoxy-4- (3-hydroxy-4-methylphenylamino) -7-methoxyquinoline-3-carbonitrile
[378] With 4-chloro-6-ethanol, 20mL of a mixture of ethoxy-7-methoxyquinoline-3-carbonitrile 1.00g (3.82mmol) and 3-hydroxy-4-methylaniline 0.563g (4.58mmol) N ₂ Lt; / RTI &gt; for 8 hours. Saturated NaHCO ₃ is added, the volatiles are removed and the residue is azeotropically mixed with ethanol. The crude product is slurried with hexane, filtered, washed with water and cold ethanol, and dried. Ethanol to give 0.632 g of 6-ethoxy-4- (3-hydroxy-4-methylphenylamino) -7-methoxyquinoline-3-carbonitrile as pale yellow crystals: mass spectrum (electrospray, m / e): M + H 349.9.
[379] Example 98
[380] Synthesis of 4-Bromo-but-2-enoic acid [4- (3-bromo-phenylamino) -3- cyano-quinolin-
[381] 1.65 g (0.01 mol) of 4-bromocrotonic acid in 15 mL of dichloromethane (Giza Braun, J. Am. Chem. Soc. 52, 3167 1930] is treated with 1.74 mL (0.02 mol) of oxalyl chloride and 1 drop of N, N-dimethylformamide. After 1 hour, the solvent is removed with a rotary evaporator. The residual oil is dissolved in 25 mL of tetrahydrofuran and 3.39 g of 6-amino-4- (3-bromo-phenylamino) -quinoline-3-carbonitrile in 25 mL of tetrahydrofuran is added dropwise. 1.92 mL (0.011 mol) of diisopropylethylamine was added dropwise thereto. After addition of 25 mL of water and 50 mL of ethyl acetate, the layers are separated. The organic layer is dried over anhydrous sodium sulfate and then transformed to a solid under vacuum. The solid was warmed to reflux with ethyl acetate for 1 hour and then filtered from still hot ethyl acetate. 3.31 g (68%) of 4-bromo-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-quinolin-6-yl] -amide are obtained.
[382] Example 99
[383] 4-Dimethylamino-but-2-enoic acid [4- (3-bromo-phenylamino) -3- cyano-quinolin-
[384] A 15 mL solution of 2M dimethylamine in tetrahydrofuran was cooled in an ice bath and a solution of 4-bromo-but-2-enoic acid 4- [3- (3-bromo-phenylamino) - cyano-quinolin-6-yl] -amide (729 mg, 1.5 mmol) was added dropwise. Stir for 2 hours and continue to cool. After this time, 25 mL of water and 15 mL of ethyl acetate are added. The layers are separated and the organic layer is extracted with 25 mL of additional water. The combined aqueous layers are extracted with 2 to 25 mL portions of tetrahydrofuran-ethyl acetate (1: 1). The combined organic layers are taken up in silica gel and chromatographed on silica gel. The column is eluted with a gradient of 1: 19 to 1: 4 methanol-methylene chloride. 381 mg (56%) of 4-dimethylamino-but-2-enoic acid [4- (3- bromo- phenylamino) -3- cyano-quinolin- %): Mass spectrum (electrospray, m / e): M + H 225.5, 226.2.
[385] Example 100
[386] Synthesis of 4-diethylamino-but-2-enoic acid [4- (3-bromo-phenylamino) -3- cyano-quinolin-
[387] A solution of 3.15 mL (30 mmol) of diethylamine in 15 mL of tetrahydrofuran was cooled in an ice bath and a solution of 4-bromo-but-2-enoic acid 4- [3- (3-bromo- Phenylamino) -3-cyano-quinolin-6-yl] -amide (729 mg, 1.5 mmol) was added dropwise. Stir for 2 hours and continue to cool. After this time, 25 mL of water and 15 mL of ethyl acetate are added. The layers are separated and the aqueous layer is extracted with 2-15 mL portions of tetrahydrofuran-ethyl acetate (1: 1). The combined organic layers are taken up in silica gel and chromatographed on silica gel. The column was eluted with a 1: 19 to 1: 4 gradient of methanol-methylene chloride to give 4-diethylamino-but-2-enoic acid [4- (3-bromo- phenylamino) Quinolin-6-yl] -amide (367 mg, 51%). The compound is melted at 141-145 占 폚 (decomposition): Mass spectrum (electrospray, m / e): M + H 478.0, 480.0.
[388] Example 101
[389] 4-methylamino-but-2-enoic acid [4- (3-bromo-phenylamino) -3- cyano-quinolin-
[390] A 15 mL solution of 2M methylamine in tetrahydrofuran was cooled in an ice bath and a solution of 4-bromo-but-2-enoic acid [4- (3-bromo-phenylamino) -3 - cyano-quinolin-6-yl] -amide (729 mg, 1.5 mmol) was added dropwise. Stir for 2 hours and continue to cool. After this time, 25 mL of water and 15 mL of ethyl acetate are added. The layers are separated and the aqueous layer is extracted with 2-15 mL portions of tetrahydrofuran-ethyl acetate (1: 1). The combined organic layers are taken up in silica gel and chromatographed on silica gel. The column is eluted with a 1: 19 to 1: 1 gradient of methanol-methylene chloride. 4-methylamino-but-2-enoic acid [4- (3-bromo-phenylamino) -3- cyano-quinolin- Amide 210 mg (32%): Mass spectrum (electrospray, m / e): M + H 437.9; M + 2H @ 219.5.
[391] Example 102
[392] 2-Cyano-3- (2-methyl-4-nitrophenyl) acrylic acid ethyl ester
[393] A mixture of 2-methyl-4-nitroaniline (38.0 g, 250 mmol), ethyl (ethoxymethylene) -cyanoacetate (50.8 g, 300 mmol) and 200 mL of toluene was refluxed for 24 h, cooled, (1: 1) and filtered. The resulting white solid (mp: 180-210 占 폚) is washed with hexane-ether and dried to give 63.9 g.
[394] Example 103
[395] 1,4-dihydroquinoline-8-methyl-6-nitro-3-carbonitrile
[396] A mixture of 64 g (230 mmol) of 2-cyano-3- (2-methyl-4-nitrophenyl) acrylic acid ester and 1.5 L of maximal A was heated at 260 ° C for 12 hours and then cooled, diluted with hexane , And filtered. The gray solid thus obtained (mp: 295-305 ° C) was washed with hexane and dried to give 51.5 g.
[397] Example 104
[398] 4-Chloro-8-methyl-6-nitro-3-quinolinecarbonitrile
[399] A stirred mixture of 1,4-dihydroquinoline-8-methyl-6-nitro-3-carbonitrile (47 g, 200 mmol) and 200 mL of phosphorus oxychloride is refluxed for 4 hours. The phosphorus oxychloride is removed in vacuo, the residue is stirred with methylene chloride at 0 &lt; 0 &gt; C and then treated with ice slurry and sodium carbonate. The organic layer is separated and washed with water. The solution is dried and then concentrated to 700 mL volume. The product was precipitated by the addition of hexane and then cooled to 0 &lt; 0 &gt; C. The white solid (mp: 210-212 占 폚) was filtered off and dried, yielding 41.6 g.
[400] Example 105
[401] 4 - [(3-bromophenyl) amino] -8-methyl-6-nitro-3-quinolinecarbonitrile
[402] 60 mmol), 3-bromoaniline (12.4 g, 72 mmol), pyridine hydrochloride (6.93 g, 60 mmol) and ethoxyethanol (80 mL, ) Is refluxed for 1.5 hours, cooled and then poured into a mixture of water and a substantial amount of sodium carbonate to give a pH of 8-9. The resulting yellow solid (mp: 263-267 [deg.] C) is filtered off, washed with water, dried, warmed in boiling ether and filtered to give 22.6 g.
[403] Example 106
[404] 4 - [(3-bromophenyl) -N-acetylamino] -8-methyl-6-nitro-3-quinolinecarbonitrile
[405] (3 mmol) of 4 - [(3-bromophenyl) amino] -8-methyl-6-nitro-3-quinolinecarbonitrile (15.3 g, 40 mmol), dimethylaminopyridine, 40 mL of acetic anhydride and 80 mmol The mixture is refluxed for 3 hours and then concentrated at 50 &lt; 0 &gt; C under vacuum. The residue is stirred with methylene chloride and 0.1N HCl. After filtration through celite, the organic layer is washed with water, dried and concentrated. The residue was chromatographed on silica gel with 1% acetic acid in methylene chloride to give 11.2 g of amber glass; NMR (CDCl ₃₎ δ2.29 (N- acetyl group).
[406] Example 107
[407] 8-Bromomethyl-4 - [(3-bromophenyl) -N-acetylamino] -6-nitro-3-quinolinecarbonitrile
[408] (10.6 g, 25 mmol), N-bromosuccinimide (6.68 g, 37.5 mmol, prepared as described in Example 1) ), 0.30 g of dibenzoyl peroxide and 200 mL of carbon tetrachloride was refluxed for 2 hours, treated with 0.30 g of additional dibenzoyl peroxide, refluxed for an additional 2.5 hours, then cooled, diluted with methylene chloride , And aqueous sodium sulfite. The organic layer is separated and washed successively with water, sodium bicarbonate solution and water. The solution was dried and evaporated to give 15 g of a white foam; _{NMR (CDCl 3) 5.19 (dd} , CH 2 Br).
[409] Example 108
[410] 4 - [(3-bromophenyl) amino] -8-dimethylaminomethyl-6-nitro-3-quinolinecarbonitrile
[411] To a dimethylamine suspension in THF (2.0 M; 115 mL; 230 mmol) was added a solution of 8-bromomethyl 4 - [(3-bromophenyl) -N- acetylamino] -6-nitro-3-quinolinecarbonitrile 11.6 g, 23 mmol) at 0 &lt; 0 &gt; C for 15 min. After raising the temperature to 25 DEG C, the mixture is stirred for 2 hours. After THF is evaporated off, the residue is refluxed with 230 mL of methanol for 1 hour along with 12.7 g (92 mmol) of potassium carbonate. The mixture is cooled, saturated with CO ₂ and then concentrated. The residue is partitioned with methylene chloride and water. The organic layer is washed with water, dried and concentrated. The residue is chromatographed on silica gel using methylene chloride-ethyl acetate-methanol-triethylamine to give 6.0 g of a yellow solid (mp: 223-226 [deg.] C).
[412] Example 109
[413] 6-Amino-4 - [(3-bromophenyl) amino] -8-dimethylaminomethyl-3-quinolinecarbonitrile
[414] (5.76 g, 14.1 mmol), iron powder (2.76 g, 49 mg-atom) and acetic acid (5.67 g, 14.1 mmol) were added to a solution of 4-amino- mL, 99 mmol) and 70 mL of methanol is refluxed for 2 hours and evaporated to remove the methanol. The residue is stirred for 10 minutes with water, the organic solid is filtered off and washed with 2% acetic acid. The total filtrate is basified to pH 5 with 5N sodium hydroxide. The resulting precipitate is extracted with methylene chloride. The extract is washed with water, dried and concentrated. The residue was chromatographed on silica gel using acetate-methanol-triethylamine to give 3.34 g of an amber solid; Mass spectrum (electrospray, m / e): M + H 396.2, 398.1.
[415] Example 110
[416] N- {4 - [(3-bromophenyl) amino] -3-cyano-8-dimethylaminomethyl-6-quinolinyl}
[417] To a stirred mixture of 2-butynoic acid (0.42 g, 5.0 mmol) and N-methylmorpholine (0.66 mL, 6.0 mmol) in 4.0 mL of THF was added i-butyl chloroformate (0.52 mL, 4.0 mmol) Add for 10 minutes. After 10 minutes, a solution of 6-amino-4 - [(3-bromophenyl) amino] -8-dimethylaminomethyl-3-quinolinecarbonitrile (0.79 g, 2.0 mmol) in 4.0 mL of THF is added over 60 seconds . The mixture is warmed to 25 &lt; 0 &gt; C, stirred for 2 hours and then diluted with water. The pH is adjusted to 9-10 with potassium carbonate, the resulting solid is filtered off, washed with water, stirred with methylene chloride and filtered. The final filtrate is concentrated to give a solid which is chromatographed on silica gel using methylene chloride-ethyl acetate-methanol-triethylamine to give an amber solid; Mass spectrum (electrospray, m / e): M + H 462, 464.
[418] Example 111
[419] N- {4 - [(3-bromophenyl) amino] -3-cyano-8-dimethylaminomethyl-6-quinolinyl} -2-propenamide
[420] A solution of 6-amino-4 - [(3-bromophenyl) amino] -8-dimethylaminomethyl-3-quinolinecarbonitrile (0.20 g, 0.50 mmol) and N, N- diisopropylethylamine 0.13 mL, 0.75 mmol). To the stirred solution was added acryloyl chloride (0.045 mL, 0.55 mmol) at 0 &lt; 0 &gt; C for 5 min. After stirring at 0 &lt; 0 &gt; C for 3 hours, the mixture is diluted with sodium bicarbonate. The resulting solid was filtered off, washed with water then dried and chromatographed on silica gel using methylene chloride-ethyl acetate-methanol-triethylamine to give a yellow solid; Mass spectrum (electrospray, m / e): M + H 449.9, 452.0.
[421] Example 112
[422] N- {4 - [(3-bromophenyl) amino] -3-cyano-8-dimethylaminomethyl-6-quinolinyl} acetamide
[423] To a stirred mixture of 6-amino-4 - [(3-bromophenyl) amino] -8-dimethylaminomethyl-3-quinolinecarbonitrile (0.20 g, 0.50 mmol) and 1.5 mL of acetic acid was added 0.14 mL mmol) at 25 &lt; 0 &gt; C. After 60 minutes, the volatiles are evaporated off under vacuum. The residue is stirred with sodium bicarbonate. The resulting solid was filtered off, washed with water, then dried and recrystallized from isopropanol-hexane to give a light yellow solid (mp: 162-167 ° C).
[424] Example 113 Synthesis of
[425] N '- [2-carbethoxy-4,5-bis (2-methoxyethoxy) phenyl] -N, N- dimethylformamidine
[426] To a stirred solution of 15.7 g (50 mmol) of ethyl 2-amino-4,5-bis (2-methoxyethoxy) -benzoate (Pfizer Patent WO 96130347) in 50 mL of DMF was added phosphorus oxychloride (5.6 mL, 60 mmol) 0.0 &gt; 0 C &lt; / RTI &gt; for 15 minutes. The resulting solution is heated at 55 &lt; 0 &gt; C for 45 min, cooled, then diluted with methylene chloride and treated with 200 mL of N / 1 sodium hydroxide at 0 &lt; 0 &gt; C for 2 min. The organic layer is separated and washed with water at 0 &lt; 0 &gt; C. The solution was dried and the added toluene was evaporated to give 18.4 g of an amber oil; _{NMR (CDCl 3) δ3.02 (s} , Me 2 N).
[427] Example 114
[428] Dihydroquinoline-5,6-bis (2-methoxyethoxy) -3-carbonitrile
[429] To a solution of n-butyllithium (44 mL; 110 mmol in 2.5 M hexane) in 65 mL of THF is added a solution of acetonitrile (5.85 mL, 112 mmol) in 110 mL of THF at -78 <0> C for 10 min. After stirring at -78 [deg.] C for 15 min, the mixture was treated with a solution of N '- [2-carboxy-4,5- Solution for 20 minutes. After 30 min at -78 [deg.] C, the stirred mixture is treated with acetic acid (14.3 mL, 250 mmol). The mixture was warmed to 25 DEG C and stirred for 2 hours. The mixture is evaporated to dryness and then diluted with water. The resulting white solid is filtered off, washed with water and dried to give 10.7 g; Mass spectrum (electrospray, m / e): M + H 319.2.
[430] Example 115
[431] 4-Chloro-5,6-bis (2-methoxyethoxy) -3-quinolinecarbonitrile
[432] A stirred mixture of 1,4-dihydroquinoline-5,6-bis (2-methoxyethoxy) -3-carbonitrile (9.68 g, 30.4 mmol) and 30 mL of phosphorus oxychloride is refluxed for 1.5 hours. The resulting solution is concentrated in vacuo and the residue is stirred with methylene chloride at O &lt; 0 &gt; C while adding ice water and sodium bicarbonate until the pH of the mixture is 8-9. The organic layer was separated, washed with water, then dried and concentrated to give a tan solid; Mass spectrum (electrospray, m / e): M + H 337.1, 339.1.
[433] Example 116
[434] 4 - [(3-ethynylphenyl) amino] -5,6-bis (2-methoxyethoxy) -3-quinolinecarbonitrile
[435] (2.52 g, 7.5 mmol), pyridine hydrochloride (0.87 g, 9.0 mmol) and 3-ethynyl aniline (1.06 g, 9.0 mmol) were added to a solution of 4-chloro-5,6- , 9.0 mmol) and ethoxyethanol (22 mL) is refluxed for 1.5 hours, cooled and then diluted with water containing sodium carbonate to a pH of about 9 and extracted with ethyl acetate. The extract is washed well with water, dried and concentrated. The resulting solid was recrystallized from ethyl acetate to give an off-white solid (mp: 150-153 &lt; 0 &gt; C).
[436] Example 117
[437] 4 - [(3-dimethylaminophenyl) amino] -5,6-bis (2-methoxyethoxy) -3-quinolinecarbonitrile
[438] (0.67 g, 2.0 mmol), pyridine (0.39 mL, 4.8 mmol), 3-dimethylaminoaniline dihydrochloride (0.50 g, 2.4 mmol) and ethoxyethanol (6.0 mL) is refluxed for 2 hours, cooled and then partitioned between ethyl acetate and water containing potassium carbonate to give a pH of about 9-10. The organic layer is washed with water, dried and concentrated. The residue was chromatographed on silica gel using methylene chloride-ethyl acetate-methanol to give an amber glass; Mass spectrum (electrospray, m / e): M + H 437.0.
[439] Example 118
[440] 4 - [(3-acetylphenyl) amino] -5,6-bis (2-methoxyethoxy) -3-quinolinecarbonitrile
[441] Chloro-5,6-bis (2-methoxyethoxy) -3-quinolinecarbonitrile was reacted with 3-aminoacetophenone to give an off-white solid (mp: 250-253 ° C) (Decomposition) of the title compound which was recrystallized from ethanol.
[442] Example 119
[443] Methyl 4-methoxy-3- (3-morpholin-4-yl-propoxy) benzoate
[444] Potassium carbonate (18.8 g, 136 mmol), tetrabutylammonium iodide (0.92 g, 2.5 mmol) were added to a solution of isobornylate (22.6 g, 124 mmol), N- (3- chloropropyl) And 248 mL of 2-butanone is refluxed for 20 hours. The 2-butanone is evaporated off and the residue is stirred at 0 &lt; 0 &gt; C with water. The resulting white solid (mp: 90-94 占 폚) is filtered off, washed successively with water and hexane, and dried.
[445] Example 120
[446] Methyl 4-methoxy-5- (3-morpholin-4-yl-propoxy) -2-nitrobenzoate
[447] (30.9 g, 100 mmol) in 100 mL of acetic acid is stirred 30 mL of 25 mL of a 70% nitric acid solution at 25 [deg.] C for 30 minutes. The solution is heated to 45 [deg.] C at which the reaction is initiated and maintained at that temperature. After a total of 1.5 h at 45-50 째 C, the mixture is cooled to 0 째 C, treated with ice water and 240 g (1.75 mmol) of potassium carbonate, and extracted with ethyl acetate. The extract is washed with water, dried and concentrated to give a yellow solid (mp: 78-82 [deg.] C).
[448] Example 121
[449] Methyl 2-amino-4-methoxy-5- (3-morpholin-4-yl-propoxy) benzoate
[450] A solution of methyl 4-methoxy-3- (3-morpholin-4-yl-propoxy) -2-nitrobenzoate (32.5 g, 91.7 mmol) in 110 mL of methanol and 220 mL of ethyl acetate was treated with 10% Pd / C catalyst 2.0 g &lt; / RTI &gt; at 55 psi. After 4 hours, the mixture is filtered and the filtrate is evaporated to dryness. The residue is recrystallized from acetone-hexane to give a tan solid (mp: 78-82 [deg.] C).
[451] Example 122
[452] Ethyl 2- (dimethylaminomethyleneamino) -4-methoxy-5- (3-morpholin-4-yl-propoxy) benzoate
[453] A mixture of 2-amino-4-methoxy-5- (3-morpholin-4-yl-propoxy) benzoate (6.49 g, 20 mmol) and dimethylformamide dimethylacetal (4.25 mL, 30 mmol) Lt; / RTI &gt; for 1.5 hours. All volatiles are removed by direct evaporation at 70 ° C to obtain a syrup; Mass spectrum (electrospray, m / e): M + H 380.5.
[454] Example 123
[455] Dihydroquinoline-7-methoxy-6- (3-morpholin-4-yl-propoxy) -4-oxo-3-carbonitrile
[456] To a solution of n-butyllithium (17.6 mL; 44 mmol in 2.5 M hexane) in 26 mL of THF was added a solution of acetonitrile (1.85 mL, 45 mmol) in THF at -78 <0> C for 10 min. After stirring at -78 [deg.] C for 15 minutes, the mixture was added to a solution of ethyl 2- (dimethylaminomethyleneamino) -4-methoxy-5- (3-morpholin-4-yl- propoxy) benzoate g, 20 mmol) solution for 20 minutes. After 90 minutes at -78 [deg.] C, the mixture was treated with carbon dioxide while slowly warming to 25 [deg.] C and then evaporated to dryness. The residue is partitioned between n-butanol (200 mL) and NaCl (40 mL). The organic layer is separated, washed with a saturated NaCl solution and evaporated to dryness. The resulting solid is successively triturated with boiling acetone and methanol, filtered and then dried to give a tan solid (mp: 255-260 ° C).
[457] Example 124
[458] 4-chloro-7-methoxy-6- (3-morpholin-4-yl-propoxy) -3-quinolinecarbonitrile
[459] Dihydroquinoline-7-methoxy-6- (3-morpholin-4-yl-propoxy) -4-oxo-3-carbonitrile (4.75 g, 13.8 mmol), DMF A stirred mixture of 55 mL thionyl is refluxed for 3 hours. The volatiles are removed by evaporation at 30 ° C and the residue is stirred at 0 ° C with a mixture of methylene chloride and water containing potassium carbonate, resulting in a pH of 9-10. The organic layer is separated, washed with water, then dried and concentrated to give a brown solid; Mass spectrum (electrospray, m / e): M + H 362.4, 364.4.
[460] Example 125
[461] 4- [(3-chloro-4-fluorophenyl) amino] -7-methoxy-6- (3-morpholin-4- yl- propoxy) -3-quinolinecarbonitrile
[462] Chloro-7-methoxy-6- (3-morpholin-4-yl-propoxy) -3-quinolinecarbonitrile (1.8 g, 5.0 mmol) , 6.0 mmol), pyridine hydrochloride (1.15 g, 10 mmol) and ethoxyethanol (15 mL) was refluxed for 2 hours, cooled, and then stirred with hexane containing potassium carbonate and water to give a pH of 10. The resulting brown solid is filtered off, washed with water and hexane, and dried. Recrystallization from ethanol gives an off-white solid (mp: 240-244 占 폚).
[463] Example 126
[464] 4- [(3-bromophenyl) amino] -7-methoxy-6- (3-morpholin-4-yl- propoxy) -3-quinolinecarbonitrile
[465] Chloro-7-methoxy-6- (3-morpholin-4-yl-propoxy) -3-quinolinecarbonitrile was reacted with 3-bromoaniline to give an off- white solid mp: 208-212 C). &lt; / RTI &gt;
[466] Example 127
[467] Amino] -7-methoxy-6- (3-morpholin-4-yl-propoxy) -3-quinolinecarbonitrile
[468] Chloro-7-methoxy-6- (3-morpholin-4-yl-propoxy) -3-quinolinecarbonitrile was reacted with 4-chloro-2-fluoroaniline to give To give the title compound which was recrystallized from methanol as an off-white solid (mp: 207-212 &lt; 0 &gt; C).
[469] Example 128
[470] 4 - [(3-hydroxy-4-methylphenyl) amino] -7-methoxy-6- (3-morpholin-
[471] Chloro-7-methoxy-6- (3-morpholin-4-yl-propoxy) -3-quinolinecarbonitrile was reacted with 3-hydroxy-4-methylaniline to give To give the title compound which was recrystallized from ethyl acetate as an amber solid (mp: 222-227 [deg.] C).
[472] Example 129
[473] N- {3-cyano-4 - [(3-iodophenyl) amino] -6- quinolinyl} -2-propenamide
[474] (1.29 mmol) of 6-amino-4 - [(3-iodophenyl) amino] -3-quinolinecarbonitrile is dissolved in 1.0 mL of DMF, and then 6 mL of THF is added. It was cooled under N ₂ to 0 ℃ then triethylamine 200㎕ chloride 120㎕ (1.44mmol) to (1.43mmol) and acrylic are added. Remove the ice bath at 15 minutes. Strip the solvent at 1.5 hours. The residue is slurried with water and then diluted with sodium bicarbonate. Collected, washed with water, and then dried in air. The solid was filtered off and the solvent of the filtrate was removed and then dried under vacuum to give 391 mg of an orangeish brown solid: Mass spectrum (electrospray, m / e): M + H = 441.1.
[475] Example 130
[476] 6-Amino-4 - [(3-iodophenyl) amino] -3-quinolinecarbonitrile
[477] 4 - by heating a mixture of [(3-iodophenyl) amino] -6-nitro-3-quinoline hydrochloride 6.70g (16.1mmol), ethanol and 300mL SnCl ₂ dianhydride 18.2g (80.5mmol) under N ₂ Reflux. Heat is removed at 2 hours and ice water is added. Sodium bicarbonate is added until the pH is basic to form a thick yellow mixture. Stir for 2.5 hours. Extraction with chloroform, stirring of the organic portion with DARKO, and filtration with magnesium sulfate. The solvent was stripped and dried in vacuo to give 3.48 g of a tan solid: Mass spectrum (electrospray, m / e): M + H 387.0.
[478] Example 131
[479] 4 - [(3-iodophenyl) amino] -6-nitro-3-quinolinecarbonitrile
[480] A mixture of 3.10 mL (25.7 mmol) of 3-iodoaniline, 200 mL of ethanol and 5.00 g (21.4 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile was heated to reflux under N ₂ for 3.5 hours. After cooling, it is made basic with saturated sodium bicarbonate. The solvent is stripped and then azeotropically mixed with ethanol. The residue is slurried with hexane and then collected. Dry in air, wash the solid with water, and dry under vacuum. The solid is dissolved in 400 mL of ethyl acetate, stirred with Darco, filtered and the solvent is removed. The solid was dried in vacuo to give 7.38 g of a yellow solid: Mass spectrum (electrospray, m / e): M + H 417.0.
[481] Example 132
[482] N- {3-cyano-4- [(3-methylphenyl) amino] -6-quinolinyl} -2-butynamide
[483] To 25 mL of THF was dissolved 597 mg (7.10 mmol) of 2-butyric acid under N _{2 and} then cooled to 0 ° C. 950 [mu] l (7.30 mmol) of isobutyl chloroformate and 780 [mu] l (7.10 mmol) of N-methylmorpholine are stirred for 10 minutes. A solution of 778 mg (2.84 mmol) of 6-amino-4 - [(3-methylphenyl) amino] -3-quinolinecarbonitrile was stirred at 0 ° C for 15 minutes and then at 25 ° C overnight. After stripping the solvent, the residue is slurried with water, and the sticky solid is simply dried under vacuum. The solid is boiled in ethyl acetate and then collected. The product was recrystallized from DMF using ethanol and triturated with water and dried under vacuum to give 401 mg of a tan solid: Mass spectrum (electrospray, m / e): M + H = 341.2.
[484] Example 133
[485] 6-Amino-4 - [(3-methylphenyl) amino] -3-quinolinecarbonitrile
[486] 253 mg of 10% Pd / C is added to the round bottom flask under N ₂ and then filled with a catalyst having 140 mL of ethanol. 2.49 g (8.18 mmol) of 6-nitro-4 - [(3-methylphenyl) amino] -3-quinolinecarbonitrile and 640 ((20.4 mmol) of hydrazine anhydride are added. The mixture is heated to reflux for 2 hours and 15 minutes, then the hot mixture is filtered through celite. The solvent was stripped and dried in vacuo to give 2.455 g of a yellow solid: Mass spectrum (electrospray, m / e): M + H 275.2.
[487] Example 134
[488] Nitro-4 - [(3-methylphenyl) amino] -3-quinolinecarbonitrile
[489] A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 mL of ethanol and 2.75 g (25.7 mmol) of 3-toluidine was heated to reflux for 4.5 hours. After cooling, saturated sodium bicarbonate is added until the pH is basic. The solvent is stripped and then azeotropically mixed with ethanol. Slurried with hexane, collected, and then dried in air. Washed with water and then dried under vacuum. Boiled in ethyl acetate, stirred with Darco and filtered. The solvent was stripped and dried under vacuum to give 4.82 g of a yellowish orange solid: Mass spectrum (electrospray, m / e): M + H = 305.2.
[490] Example 135
[491] N- {4 - [(3-chlorophenyl) amino] -3-cyano-6-quinolinyl} -2-propenamide
[492] 430 mg (1.46 mmol) of 6-amino-4 - [(3-chlorophenyl) amino] -3-quinolinecarbonitrile are dissolved in 4 mL of DMF, 10 mL of THF is added and the mixture is cooled to 0 ° C under N ₂ . 224 [mu] L (1.60 mmol) of triethylamine and 133 mu l (1.60 mmol) of acryloyl chloride are added. The ice bath was removed at 15 minutes and the reaction was completed at that time but stirred at 25 &lt; 0 &gt; C overnight. The solvent is stripped, dilute sodium bicarbonate is added to the residue, and the solid is collected. Washed with water and then dried under vacuum. Boiling in ethyl acetate and collecting the solid and drying in vacuo afforded 200 mg of an orange solid: Mass spectrum (electrospray, m / e): M + H = 349.0, 351.0.
[493] Example 136
[494] 6-Amino-4 - [(3-chlorophenyl) amino] -3-quinolinecarbonitrile
[495] 4 - [(3-chlorophenyl) amino] refluxed by heating a mixture of 6-nitro-3-quinoline hydrochloride 6.30g (19.4mmol), ethanol and 300mL SnCl ₂ 21.9g (97mmol) under N _2. Heat is removed at 2.5 hours, ice water is added, and the mixture is made basic with sodium bicarbonate. Stir 2 h and then extract with chloroform. The organic layer was dried with sodium sulfate, filtered and the solvent was stripped and the residue was dried under vacuum to give 5.74 g of a tan solid: Mass spectrum (electrospray, m / e): M + H = 295.1, 297.1.
[496] Example 137
[497] 4 - [(3-chlorophenyl) amino] -6-nitro-3-quinolinecarbonitrile
[498] A mixture of 10.0 g (42.9 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile, 260 mL of ethanol and 5.40 mL of 3-chloroaniline was heated to reflux under N ₂ for 3.5 hours. Heat is removed at 4 hours, cooled to 25 ° C, and saturated sodium bicarbonate is added until the pH is basic. The solvent is stripped and then azeotropically mixed with ethanol. The residue is slurried with hexane, the solid is collected and dried in air. The solid is washed with water and then dried under vacuum. Dissolved in boiling ethyl acetate, stirred with Darco and filtered. The solvent was stripped and the residue was dried in vacuo to give 6.5 g of a yellow solid: Mass spectrum (electrospray, m / e): M + H 325.0, 327.0.
[499] Example 138
[500] N- {3-cyano-4 - [(3-methoxyphenyl) amino] -6- quinolinyl} -2-propenamide
[501] 500 mg (1.72 mmol) of 6-amino-4 - [(3-methoxyphenyl) amino] -3-quinolinecarbonitrile is dissolved in 2 mL of hot DMF, 6 mL of THF is added and then cooled to 0 占 폚. 264 [mu] l (1.90 mmol) of triethylamine and 158 [mu] l (1.90 mmol) of acryloyl chloride are added. Remove the ice bath at 15 minutes. Strip the solvent at 2 hours. The residue is washed with dilute sodium bicarbonate, and the solid is collected, washed with water and dried in air. The solid was boiled in ethyl acetate, collected and dried in vacuo to give 288 mg of a yellowish orange solid: Mass spectrum (electrospray, m / e): M + H = 345.2.
[502] Example 139
[503] N- {3-cyano-4 - [(3-methoxyphenyl) amino] -6- quinolinyl} -2-butynamide
[504] To 20 mL of THF was dissolved 362 mg (4.31 mmol) of the acid under N _{2 and} then cooled to 0 ° C. (4.30 mmol) of isobutyl chloroformate and 475 [mu] L (4.31 mmol) of N-methylmorpholine are added, and the mixture is stirred for 10 minutes. 500 mg (1.72 mmol) of 6-amino-4 - [(3-methoxyphenyl) amino] -3-quinolinecarbonitrile is dissolved in 2 mL of hot DMF and then 10 mL of THF is added. The mixed anhydride is added dropwise thereto, and the mixture is stirred at 0 ° C for 15 minutes and then at 25 ° C overnight. The solvent is stripped, the residue is slurried with water, the solid is collected and dried in air. Recrystallization from ethyl acetate and drying under vacuum afforded 270 mg of a yellow solid: Mass spectrum (electrospray, m / e): M + H 357.1.
[505] Example 140
[506] N- {3-cyano-4 - [(3-methoxyphenyl) amino] -6-quinolinyl} -4-piperidino-
[507] In 100mL THF it was partially dissolved 4- piperidino-2-butyric acid 1.21g (7.22mmol) and then cooled to, 0 ℃ under N _2. 955 [mu] L (8.67 mmol) of N-methylmorpholine and 750 [mu] L (5.78 mmol) of isobutyl chloroformate are added. After stirring for 40 minutes, a solution of 840 mg (2.89 mmol) of 6-amino-4 - [(3-methoxyphenyl) amino] -3-quinolinecarbonitrile dissolved in 10 mL of hot pyridine is added. After 2 hours pour into ice water and make it basic with saturated sodium bicarbonate. Extracted with ethyl acetate, dried over sodium sulfate, stripped vigorously and loaded onto a silica gel column. Elution with 10% methanol / ethyl acetate and stripping of the solvent from the desired fractions followed by drying in vacuo afforded 970 mg of a green solid: Mass spectrum (electrospray, m / e): M + H 440.1.
[508] Example 141
[509] 6-Amino-4 - [(3-methoxyphenyl) amino] -3-quinolinecarbonitrile
[510] 325 mg of 10% Pd / C is added to the round bottom flask under N ₂ and then filled with 165 mL of ethanol. 3.29 g (10.3 mmol) of 4 - [(3-methoxyphenyl) amino] -6-nitro-3-quinolinecarbonitrile and 800 하 of hydrazine anhydride were added and the mixture was heated to reflux. At 1.5 hours the hot mixture was filtered through celite, stripping the solvent and drying in vacuo to give 2.876 g of a yellow solid: Mass spectrum (electrospray, m / e): M + H 291.2.
[511] Example 142 [
[512] 4 - [(3-methoxyphenyl) amino] -6-nitro-3-quinolinecarbonitrile
[513] A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 mL of ethanol and 3.0 mL (26.0 mmol) of m-anisidine is heated to reflux under N ₂ . Heat is removed at 4.5 hours and then made basic with saturated sodium bicarbonate. The solvent is stripped and then azeotropically mixed with ethanol. After slurrying with hexane, the crystals are collected. Washed with water and then dried under vacuum. 5.94 g of the crude product are dissolved in 320 ml of boiling ethyl acetate and stirred with Dharcoal followed by filtration, solvent removal and drying in vacuo to give about 5 g of a yellowish orange solid: mass spectrum , &lt; / RTI &gt; m / e): M + H 291.1.
[514] Example 143
[515] N- {4- [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl}
[516] To 20 mL of THF was dissolved 336 mg (4.00 mmol) of 2-butynoic acid and then cooled to 0 ° C under N ₂ . (4.00 mmol) of isobutyl chloroformate and 440 쨉 L (4.00 mmol) of N-methylmorpholine were added, and the mixture was stirred for 10 minutes. (1.60 mmol) of 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -3-quinolinecarbonitrile was added and stirred for 15 minutes at 0 &Lt; / RTI &gt; The solvent is stripped, washed with water, then collected, and dried under vacuum. Recrystallization from ethyl acetate gave 148 mg of a yellow solid: Mass spectrum (electrospray, m / e): M + H = 379.1, 381.1.
[517] Example 144
[518] N- {4- [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -2-propenamide
[519] In hot DMF 2mL 6- amino-4 - [(3-chloro-4-fluorophenyl) amino] quinoline-3-carbonitrile was dissolved 1.00g (3.20mmol) was added to 12mL THF and then, under N ₂ 0 &lt; 0 &gt; C. 490 [mu] l (3.52 mmol) of triethylamine and 295 [mu] l (3.52 mmol) of acryloyl chloride are added. The ice bath is removed at 15 minutes, and the solvent is removed at 1.5 hours. The residue is slurried with dilute sodium bicarbonate, the solid is collected and washed with water. Recrystallization from ethyl acetate gave 215 mg of a yellow solid: Mass spectrum (electrospray, m / e): M + H 367.1, 369.1.
[520] Example 145
[521] N- {4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -4-dimethylamino-
[522] 1.50 g (4.80 mmol) of 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -3-quinolinylcarbonitrile was dissolved in 50 mL of THF and N, N-diisopropylethylamine was added 836㎕ (4.80mmol) and then cooled under a, N ₂ to 0 ℃. (4.80 mmol) of 4-bromo-but-2-enoyl chloride is added and after 1 hour the mixture is added dropwise to 10 mL of a 2 M dimethylamine solution (19 mmol) in THF cooled to -78 &lt; 0 &gt; C. At the second hour, 5 ml (9.5 mmol) or more of dimethylamine solution is added and the temperature is raised to 25 占 폚. After 1 hour, pour into cold sodium bicarbonate solution. Extraction is carried out with ethyl acetate, and the organics are dried with brine and sodium sulfate, reduced to a small extent, and then loaded onto a silica gel column. Elution with 70% methanol / ethyl acetate and stripping of the solvent from the desired fractions followed by drying in vacuo afforded 427 mg of a yellow solid: Mass spectrum (electrospray, m / e): M + H 424.0, 426.0.
[523] Example 146
[524] N - {4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl}
[525] (4.80 mmol) of 4-bromo-but-2-enoyl chloride was added dropwise to a solution of 1.50 g of 6-amino-4 - [(3- chloro-4- fluorophenyl) amino] -3-quinolinecarbonitrile (4.80mmol) and N, N- di-isopropyl ethyl amine was added at 0 ℃ under N ₂ in 836㎕ (4.80mmol). After 1 hour the mixture is added dropwise to 1.26 mL (24 mmol) of diethylamine in 11 mL of THF cooled to -78 &lt; 0 &gt; C. After complete addition, the dry ice bath is removed and poured into a mixture of ice and saturated sodium bicarbonate at 2 hours 45 minutes. Extraction with ethyl acetate, drying of the organic layer with brine and sodium sulfate, and stripping of the solvent. The compound was loaded onto a silica gel column and eluted with 35% methanol / ethyl acetate, then the solvent was removed from the desired fractions and dried under vacuum to give 292 mg of a yellowish orange solid: mass spectrum (electrospray, m / e): M + H 452.4, 454.4.
[526] Example 147
[527] N- {4- [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -4-morpholino-2-butenamide
[528] (4.80 mmol) of 4-bromo-but-2-enoyl chloride was added dropwise to a solution of 1.50 g of 6-amino-4 - [(3- chloro-4- fluorophenyl) amino] -3-quinolinecarbonitrile (4.80mmol) and N, N- di-isopropyl ethyl amine was added at 0 ℃ under N ₂ in 836㎕ (4.80mmol). At 1 hour, the mixture is added dropwise to 2.09 mL (24 mmol) of morpholine in 10 mL of THF at 0 &lt; 0 &gt; C. After the addition is complete, the ice bath is removed and, after 3 hours, the reaction is poured into a mixture of ice and saturated sodium bicarbonate. Extraction with ethyl acetate, drying of the organic layer with brine and sodium sulfate, and stripping of the solvent. The compound was loaded onto a silica gel column and eluted with 12% methanol / ethyl acetate then the solvent was removed from the desired fractions and dried under vacuum to give 798 mg of a yellow solid: mass spectrum (electrospray, m / e ): M &lt; + &gt; H 466.4, 468.4.
[529] Example 148
[530] N- {4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -2-morpholin-
[531] 1.37 g (8.00 mmol) of 2-morpholin-4-ylmethyl-2-propenoic acid are partially dissolved in 50 mL of THF and then cooled to 0 ° C under N ₂ . 1.06 mL (9.6 mmol) of N-methyl-morpholine and 833 [mu] L (6.4 mmol) of isobutyl chloroformate are added. After stirring for 1 hour at 0 ° C, a solution of 1.00 g (3.20 mmol) of 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -3-quinolinecarbonitrile in 5 mL of pyridine is added. Stir overnight at 25 &lt; 0 &gt; C. Poured into a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, and then the organic layer is dried with brine and sodium sulfate and the solvent is stripped vigorously. After loading onto a silica gel column and elution with 1% methanol / ethyl acetate, the solvent was removed from the desired fractions and then dried under vacuum to give 139 mg of a yellowish orange solid: mass spectrum (electrospray, m / e): M + H 465.8, 468.0
[532] Example 149
[533] 6-Amino-4 - [(3-chloro-4-fluorophenyl) amino] -3-quinolinecarbonitrile
[534] 4 - A mixture of [(3-chloro-4-fluorophenyl) amino] -6-nitro-quinoline-3-carbonitrile 5.360g (15.6mmol), ethanol and 250mL SnCl ₂ dianhydride 17.67g (78.2mmol) N ₂ under reflux. Remove heat at 1.5 hours and add ice water. Make basic with sodium bicarbonate. Stir 2 h and then extract with chloroform. Brine is added to the separation funnel to assist in layer separation. The organic layer is stirred with DARKO and then dried with sodium sulfate. Filtration and stripping of the solvent followed by drying in vacuo afforded 4.460 g of a tan solid: Mass spectrum (electrospray, m / e): M + H = 312.9, 315.0.
[535] Example 150
[536] 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-3-quinolinecarbonitrile
[537] 5.00 g (21.5 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile A mixture of 200 mL of ethanol and 3.75 g (25.8 mmol) of 3-chloro-4-fluoroaniline was heated to reflux under N ₂ . Remove the heat at 3.5 hours and then add saturated sodium bicarbonate until the mixture becomes basic. The solvent is stripped and then azeotropically mixed with ethanol. The residue is slurried with hexane, the solid is collected, washed with water and dried under vacuum. The solid is dissolved in 250 mL of boiling ethyl acetate, stirred with Darco and filtered. The solvent was stripped and dried under vacuum to give 6.036 g of a yellow solid: Mass spectrum (electrospray, m / e): M + H = 343.1, 345.1.
[538] Example 151
[539] N- {4 - [(4-bromophenyl) amino] -3-cyano-6-quinolinyl} -2-propenamide
[540] Hot 6-amino-4 in DMF 1mL - dissolving [(4-bromophenyl) amino] quinoline-3-carbonitrile 500mg (1.47mmol) and, the addition of 6mL THF and then cooled under N ₂ to 0 ℃ . 226 [mu] L (1.62 mmol) triethylamine and 135 [mu] L (1.62 mmol) acryloyl chloride are added. Remove the ice bath at 15 minutes. At 1.5 h the solvent was stripped and the residue was slurried with dilute sodium bicarbonate, then the solids were collected and dried under vacuum. The solid was boiled in ethyl acetate, collected and dried in vacuo to give 194 mg of a yellowish orange solid: Mass spectrum (electrospray, m / e): M + H 393.1, 395.1.
[541] Example 152
[542] 6-Amino-4 - [(4-bromophenyl) amino] -3-quinolinecarbonitrile
[543] 4 - [(4-bromophenyl) amino] by heating a mixture of 6-nitro-quinoline-3-carbonitrile 3.10g (8.40mmol), 155mL of ethanol, and SnCl ₂ complete water 9.47g (42.0mmol) under N ₂ Reflux. Heat is removed at 4 hours and ice water is added. Made basic with sodium bicarbonate, and then stirred for 2 hours. The mixture is still basic and extracted with chloroform, then the organic layer is stirred with DARKO and dried with sodium sulfate. Filtration and stripping of the solvent followed by drying in vacuo afforded 2.265 g of a brownish yellow solid: Mass spectrum (electrospray, m / e): M + H = 339.0, 341.0.
[544] Example 153
[545] 4 - [(4-bromophenyl) amino] -6-nitro-3-quinolinecarbonitrile
[546] 5.00 g (21.5 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile A mixture of 200 mL of ethanol and 4.42 g (25.8 mmol) of p-bromoaniline was heated to reflux under N ₂ for 3 h. Heat is removed and saturated sodium bicarbonate is added until basic. The solvent is stripped and then azeotropically mixed with ethanol. The residue is slurried with hexane, the solid is collected and dried in air. Washed with water and then dried under vacuum. Boiling in 1.4 L of ethyl acetate, stirring all the solids completely without dissolving, and then filtering. The solvent was stripped and dried in vacuo to give 3.524 g of a yellow solid: Mass spectrum (electrospray, m / e): M + H = 369, 370.9.
[547] Example 154
[548] N- {3-cyano-4 - [(3,4-difluorophenyl) amino] -6- quinolinyl} -2-propenamide
[549] In 2mL DMF 6- amino-4-one dissolved [(3,4-difluorophenyl) amino] quinoline-3-carbonitrile 1.00g (3.37mmol) was added to 12mL THF and then, under N ₂ 0 ℃ Lt; / RTI &gt; 517 [mu] l (3.71 mmol) of triethylamine and 310 [mu] l (3.72 mmol) of acryloyl chloride are added. Remove the ice bath at 15 minutes. After 3.5 hours the solvent is stripped off and the residue is slurried with dilute sodium bicarbonate. The solid is collected, washed with water and then dried in air. Boiling in ethyl acetate and collecting the solid and drying in vacuo afforded 332 mg of a yellow solid: Mass spectrum (electrospray, m / e): M + H 351.1.
[550] Example 155
[551] 6-Amino-4 - [(3,4-difluorophenyl) amino] -3-quinolinecarbonitrile
[552] 4 - A mixture of [(3,4-difluorophenyl) amino] -6-nitro-3-quinoline hydrochloride 4.53g (13.9mmol), ethanol and 200mL SnCl ₂ complete water 15.72g (69.4mmol) N ₂ To reflux. Heat is removed at 1.5 hours, ice water is added, and then basified with sodium bicarbonate. Stir 2 h and then extract with chloroform. The organic layer is stirred with Dharcoa, dried over sodium sulfate and filtered. The solvent was stripped and dried in vacuo to give 3.660 g of a yellowish green solid: Mass spectrum (electrospray, m / e): M + H = 297.1.
[553] Example 156
[554] 4 - [(3,4-difluorophenyl) amino] -6-nitro-3-quinolinecarbonitrile
[555] A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile, 250 mL of ethanol and 2.55 mL (25.8 mmol) of 3,4-difluoroaniline is heated to reflux under N ₂ for 3.5 hours The heat is removed and made basic with sodium bicarbonate. The solvent is stripped and then azeotropically mixed with ethanol. The residue is slurried with hexane, the solid is collected and dried in air. Washed with water and then dried under vacuum. Mass spectrum (electrospray, m / e): M + H = &lt; / RTI &gt;&lt; RTI ID = 0.0 &gt; 327.1.
[556] Example 157
[557] N- {4 - [(3-chloro-4-thiophenoxyphenyl) amino] -3-cyano-6-quinolinyl}
[558] To 40 mL of THF is dissolved 314 mg (3.72 mmol) of _2- butynoic acid under N2. After cooling to 0 캜, 409 ㎕ (3.72 mmol) of N-methylmorpholine and 485 ㎕ (3.72 mmol) of isobutyl chloroformate are added and stirred for 10 minutes. A solution prepared by dissolving 1.00 g (2.48 mmol) of 6-amino-4 - [(3-chloro-4-thiophenoxy) amino] -3-quinolinecarbonitrile in 2.0 mL of hot DMF was added dropwise, Add 20 mL of THF. The mixture is stirred at 0 &lt; 0 &gt; C for 15 minutes and then at 25 &lt; 0 &gt; C overnight. The reaction is driven to completion and 1.24 mmol of the mixed anhydride in 15 mL of THF (104 mg of acid, 136 μL of NMM and 161 μL of isobutyl chloroformate) is added. Stir overnight. The solvent is stripped and then dried under vacuum. Recrystallization from ethyl acetate and drying in vacuo afforded 284 mg of a yellowish orange solid: Mass spectrum (electrospray, m / e): M + H 469.2, 471.2.
[559] Example 158
[560] 6-Amino-4 - [(3-chloro-4-thiophenoxyphenyl) amino] -3-quinolinecarbonitrile
[561] A mixture of 6.753 g (15.6 mmol) of 4 - [(3-chloro-4-thiophenoxyphenyl) amino] -6-nitro-3-quinolinecarbonitrile, 250 mL of ethanol and 17.66 g (78.0 mmol) of SnCl ₂ dihydrate Is heated under N ₂ and refluxed. Heat is removed at 2 hours, a large amount of ice water is added, and the mixture is made basic with sodium bicarbonate. Stir 2 h and extract with chloroform using a mixture that is still basic. The organic layer was stirred with DARKO, dried with sodium sulfate, filtered, stripped of solvent and then dried under vacuum to give 5.996 g of a tan solid: Mass spectrum (electrospray, m / e): M + H = 403.1, 405.1.
[562] Example 159
[563] 4 - [(3-chloro-4-thiophenoxyphenyl) amino] -6-nitro-3-quinolinecarbonitrile
[564] A mixture of 4-chloro-6-nitro-3-quinoline hydrochloride 5.00g (21.5mmol), ethanol and 250mL 3-chloro-4-thiophenoxy aniline 6.07g (25.6mmol) then heated to reflux under N ₂ . Heat is removed at about 8 hours and made basic with sodium bicarbonate, then the solvent is stripped and azeotropically mixed with ethanol. The residue is slurried with hexane and the solid is collected. Washed with water and then dried under vacuum. It is almost completely dissolved in 40 mL of ethyl acetate, stirred with Darco and filtered. Strip the solvent and boil it in hexane to remove any excess aniline. Drying in vacuo afforded 6.90 g of a red solid: Mass spectrum (electrospray, m / e): M + H = 433.1, 435.1.
[565] Example 160
[566] N- {3-cyano-4 - [(3-cyanophenyl) amino] -6- quinolinyl} -2-propenamide
[567] 729 mg (2.56 mmol) of 6-amino-4 - [(3-cyanophenyl) amino] -3-quinolinecarbonitrile are dissolved in 2 ml of hot DMF, 12 ml of THF are added and then cooled to 0 ° C under N ₂ . 392 [mu] L (2.81 mmol) of triethylamine and 234 [mu] L (2.81 mmol) of acryloyl chloride are added. After 15 minutes, the ice bath is removed and the solvent is stripped at 2 hours. The residue is washed with water and the solid is collected. Recrystallization from ethyl acetate and drying under vacuum gave 318 mg of a yellow solid: Mass spectrum (electrospray, m / e): M + H 340.1.
[568] Example 161
[569] N- {3-cyano-4 - [(3-cyanophenyl) amino] -6- quinolinyl} -4-piperidino-
[570] 1.46 g (8.75 mmol) of 4-piperidino-2-butynoic acid are partially dissolved in 100 mL of THF and then cooled to 0 ° C under N ₂ . 1.16 mL (10.5 mmol) of N-methylmorpholine and 911 (7.00 mmol) of isobutyl chloroformate are added and stirred for 30 minutes. A solution of 1.00 g (3.50 mmol) of 6-amino-4 - [(3-cyanophenyl) amino] -3-quinolinecarbonitrile was added to 8 mL of pyridine. It is poured into an ice bath at 3.5 hours and then made basic with saturated sodium bicarbonate. Extraction with ethyl acetate, drying of the organic layer with magnesium sulfate, followed by filtration, the solvent is reduced slightly. The compound is loaded onto a silica gel column and then eluted with 7% methanol / ethyl acetate. The solvent was stripped from the desired fractions and then dried under vacuum to afford 1.008 g of an off-white solid: Mass spectrum (electrospray, m / e): M + H 435.0.
[571] Example 162
[572] 6-Amino-4 - [(3-cyanophenyl) amino] -3-quinolinecarbonitrile
[573] 100 mg of 10% Pd / C is added to the round bottom flask under N ₂ and then filled with 50 mL of ethanol. 1.00 g (3.17 mmol) of 4 - [(3-cyanophenyl) amino] -6-nitro-3-quinolinecarbonitrile and 250 μl (7.39 mmol) of hydrazine anhydride were added and heated to reflux. Heat is removed at 2 hours and the hot mixture is filtered through celite. The solvent was stripped and dried under vacuum to give 887 mg of a yellow solid: Mass spectrum (electrospray, m / e): M + H 286.2.
[574] Example 163
[575] 4 - [(3-cyanophenyl) amino] -6-nitro-3-quinolinecarbonitrile
[576] A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 mL of ethanol and 3.04 g (25.8 mmol) of 3-aminobenzonitrile is heated and refluxed. Heat is removed at 3.5 hours and then made basic with sodium bicarbonate. The solvent is stripped and then dried in air. The residue is slurried with hexane and the solid is collected. Washed with water and then dried under vacuum. The bulk of the ethyl acetate was boiled and the solid was collected and dried under vacuum to give 5.15 g of a tan solid: Mass spectrum (electrospray, m / e): M + H = 316.0.
[577] Example 164
[578] N- {3-cyano-4 - [(3-ethynylphenyl) amino] -6- quinolinyl} -2-butynamide
[579] To 20 mL of THF was dissolved 370 mg (4.40 mmol) of _2- butynoic acid under N _{2 and} then cooled to 0 ° C. 484 [mu] L (4.40 mmol) of N-methylmorpholine and 572 [mu] L (4.40 mmol) of isobutyl chloroformate are added and stirred for 10 minutes. A solution of 500 mg (1.76 mmol) of 6-amino-4 - [(3-ethynylphenyl) amino] -quinoline-3-carbonitrile is added to 1 mL of DMF and 10 mL of THF. The ice bath is removed on the 15th minute, and the mixture is stirred overnight at 25 ° C. The solvent is stripped, the residue is slurried with water, and the solid is collected and dried under vacuum. Boiling in ethyl acetate and collecting the solid and drying in vacuo afforded 494 mg of a yellow solid: Mass spectrum (electrospray, m / e): M + H 350.9.
[580] Example 165
[581] N- {3-cyano-4 - [(3-ethynylphenyl) amino] -6- quinolinyl} -2-propenamide
[582] In hot DMF 2mL 6- amino-4 - [(3-ethynyl-phenyl) amino] quinoline-3-carbonitrile was dissolved 1.00g (3.52mmol), was added 12mL THF, and then cooled under N ₂ to 0 ℃ . 539 [mu] l (3.87 mmol) of triethylamine and 322 [mu] l (3.87 mmol) of acryloyl chloride are added. The ice bath is removed at 15 minutes and the solvent is stripped at 1.5 hours. The residue is slurried with water, the solid is collected and dried overnight. Recrystallization from ethyl acetate and drying in vacuo afforded 302 mg of an orange solid: Mass spectrum (electrospray, m / e): M + H 339.1.
[583] Example 166
[584] N- {3-cyano-4 - [(3-ethynylphenyl) amino] -6- quinolinyl} -4-piperidino-
[585] 1.03 g (6.16 mmol) of 4-piperidino-2-butynoic acid was partially dissolved in 70 mL of THF and then cooled to 0 ° C under N ₂ . (7.38 mmol) of N-methylmorpholine and 640 占 (4.92 mmol) of isobutyl chloroformate are added. After stirring for 0.5 h, a solution of 700 mg (2.46 mmol) of 6-amino-4 - [(3-ethynylphenyl) amino] -3-quinolinecarbonitrile dissolved in 5 mL of pyridine was added. It is poured into an ice bath for an hour and then made basic with saturated sodium bicarbonate solution. Extracted with ethyl acetate and the organics dried with sodium sulfate, reduced slightly and loaded onto a silica gel column. Elution with 8% methanol in ethyl acetate. The solvent was stripped from the desired fractions and dried under vacuum to give 641 mg of a yellowish orange solid: Mass spectrum (electrospray, m / e): M + H 434.2.
[586] Example 167
[587] 6-Amino-4 - [(3-ethynylphenyl) amino] -3-quinolinecarbonitrile
[588] 4 - A mixture of [(3-ethynyl-phenyl) amino] -6-nitro-3-quinoline hydrochloride 2.00g (6.36mmol), 100mL methanol and SnCl ₂ complete water 7.19g (31.8mmol) was heated under N ₂ Reflux. Remove heat at 3.5 hours and add ice water. Made basic with sodium bicarbonate, and then stirred for 2 hours. The organic layer was extracted with chloroform, the organic layer was stirred with dichloro, dried with sodium sulfate, filtered and the solvent was stripped and dried in vacuo to give 1.737 g of a tan solid: mass spectrum (electrospray, m / e): M + H = 285.2.
[589] Example 168
[590] 4 - [(3-ethynylphenyl) amino] -6-nitro-3-quinolinecarbonitrile
[591] A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 mL of ethanol and 3.82 g (32.6 mmol) of 3-ethynyl aniline was heated to reflux under N ₂ . Remove heat at 3.5 hours and add saturated sodium bicarbonate solution until basic. The solvent is stripped and then azeotropically mixed with ethanol. The residue is slurried with hexane and the solid is collected. Washed with water and then dried under vacuum. After dissolving in ethyl acetate and stirring with Darco, the solvent was stripped and dried under vacuum to give 4.544 g of a yellow solid: Mass spectrum (electrospray, m / e): M + H = 315.1.
[592] Example 169
[593] N- {4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl} -4-piperidino-
[594] 1.23 g (7.37 mmol) of 4-piperidino-2-butynoic acid are partially dissolved in 40 mL of THF and then cooled to 0 ° C under N ₂ . 973 [mu] L (8.4 mmol) of N-methylmorpholine and 768 [mu] L (5.9 mmol) of isobutyl chloroformate are added. After stirring for 10 minutes, a solution of 1.00 g (2.95 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile in 2 mL of DMF and 10 mL of THF is added. On the 15th and 5th hours, the ice bath was removed and 2.95 mmol or more of a mixed anhydride (0.493 g of acid, 487 NM of NMM and 384 ㎕ of isobutyl chloromorphate) was added, followed by stirring at 25 째 C overnight. The solvent is stripped, the residue is slurried with water and the solid is collected. It is boiled in ethyl acetate and then collected. Dissolved in 20% methanol / chloroform, and then coated with 5 g of silica gel. Flash chromatography using 20% methanol / ethyl acetate and stripping of solvent from the desired fractions followed by drying in vacuo afforded 122 mg of a brown solid: Mass spectrum (electrospray, m / e): M + H 488.0, 489.9.
[595] Example 170
[596] N- {4- [(3-bromophenyl) amino] -3-cyano-6-quinolinyl} -4-dipropylamino-2-butynamide
[597] 1.28 g (7.0 mmol) of 4-dipropylamino-2-butynoic acid are partially dissolved in 100 ml of THF and then cooled to 0 ° C under N ₂ . 974 占 퐇 (8.85 mmol) of N-methylmorpholine and 768 占 (5.90 mmol) of isobutyl chloroformate are added and stirred for 30 minutes. A solution of 1.00 g (2.95 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile was added to 8 mL of pyridine. After 2 hours, the mixture was quenched with ice water and extracted with ethyl acetate. The organic layer is dried with magnesium sulfate, the solvent is reduced slightly, and then loaded onto a silica gel column. Elution with ethyl acetate and removal of the solvent from the desired fractions followed by drying in vacuo afforded 764 mg of a yellow solid: Mass spectrum (electrospray, m / e): M + H 504, 506.4.
[598] Example 171
[599] N- {4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl} -2-morpholin-
[600] 1.26 g (7.37 mmol) of 2-morpholin-4-ylmethyl-2-propenoic acid are partially dissolved in 40 mL of THF and then cooled to 0 ° C under N ₂ . 810 [mu] L (7.37 mmol) of N-methylmorpholine and 950 [mu] L (7.37 mmol) of isobutyl chloroformate are added. After stirring for 10 minutes, a solution of 1.00 g (2.95 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile is added to 2.5 mL of DMF and 20 mL of THF. At 2 hours the solvent is stripped, the residue is slurried with water and the solids are collected and dried under vacuum. Recrystallization from ethyl acetate and drying in vacuo afforded 334 mg of a yellowish orange solid: Mass spectrum (electrospray, m / e): M + H 492, 494.3.
[601] Example 172
[602] N- {4 - [(3-bromo-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -4-dimethylamino-
[603] (2.25 mmol) of trimethylsilyl 4-bromo-but-2-enoate, 10 mL of methylene chloride, 294 L (3.38 mmol) of oxalyl chloride and 2 drops of DMF were mixed to give 5-bromo- Yielding 2.25 mmol of monochloride. After the bubbling settling, the solvent is stripped and then dissolved in 10 mL of THF. (2.25 mmol) of 6-amino-4 - [(3-bromo-4-fluorophenyl) amino] -3-quinolinecarbonitrile cooled to 0 C under N ₂ , 50 mL of THF, (392 [mu] l (2.25 mmol) of diisopropylethylamine. Is added dropwise to a solution of 5.62 mL of 2.0 M dimethylamine in THF (11.2 mmol) at -78 &lt; 0 &gt; C. After complete addition, remove the dry ice bath. After 2 hours, it is poured into a cold sodium bicarbonate solution, extracted with ethyl acetate, the organic layer is dried with sodium sulfate and the solvent is reduced vigorously. Loaded onto a silica gel column, and then eluted with 50% methanol / ethyl acetate. The solvent was stripped from the desired fractions and dried under vacuum to give 386 mg of a yellow solid: Mass spectrum (electrospray, m / e): M + H 467.9, 469.9.
[604] Example 173
[605] N- {4- [(3-bromo-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -4-diethylamino-2-butenamide
[606] (2.25 mmol) of trimethylsilyl 4-bromo-but-2-enoate, 10 mL of methylene chloride, 294 L (3.38 mmol) of oxalyl chloride and 2 drops of DMF were mixed to give 5-bromo- Yielding 2.25 mmol of monochloride. After the bubbling settling, the solvent is stripped and then dissolved in 10 mL of THF. 6-amino-4 cooled to 0 ℃ to the solution under N ₂ - [(3- bromo-4-fluoro-phenyl) amino] quinoline-3-carbonitrile 800mg (2.25mmol), THF 50mL, DMF 3mL ( Amine) and 392 [mu] L (2.25 mmol) N, N-diisopropylethylamine. Remove the ice bath at 20 minutes. Was added dropwise to a solution of 1.2 mL (11.2 mmol) of diethylamine in 4.4 mL of THF cooled to -78 &lt; 0 &gt; C. After complete addition, the dry ice bath is removed and stirred for 3 hours. Poured into a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, and then the organic layer is dried with sodium sulfate and the solvent is reduced vigorously. The compound was loaded onto a silica gel column and eluted with 30% methanol / ethyl acetate, then the solvent was stripped from the desired fractions and dried under vacuum to give 321 mg of a tan solid: mass spectrum (electrospray, m / e ): M + H 496.0, 497.9.
[607] Example 174
[608] N- {4- [(3-bromo-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -4-morpholino-2-butenamide
[609] (2.25 mmol) of trimethylsilyl 4-bromo-but-2-enoate, 10 mL of methylene chloride, 294 L (3.38 mmol) of oxalyl chloride and 2 drops of DMF were mixed to give 5-bromo- Yielding 2.25 mmol of monochloride. After the bubbling settling, the solvent is stripped and then dissolved in 10 mL of THF. (2.25 mmol) of 6-amino-4 - [(3-bromo-4-fluorophenyl) amino] -3-quinolinecarbonitrile cooled to 0 C under N ₂ , 50 mL of THF, (392 [mu] l (2.25 mmol) of diisopropylethylamine. After 1 hour the mixture is added dropwise to a solution of morpholine (1 mL, 11.2 mmol) in 4.5 mL of THF cooled to 0 &lt; 0 &gt; C. After thoroughly adding, the ice bath is removed and poured into a mixture of ice and saturated sodium bicarbonate at 2 hours. Extraction is carried out with ethyl acetate, the organic layer is dried with sodium sulfate and the solvent is reduced in small amount. The residue was chromatographed on silica gel column, eluting with 12% methanol / ethyl acetate, stripping the solvent from the desired fractions and drying in vacuo to give 369 mg of a yellow solid: mass spectrum (electrospray, m / e) M &lt; + &gt; H 509.9, 511.9.
[610] Example 175
[611] N- {4 - [(3-bromo-4-fluorophenyl) amino] -3-cyano-7-methoxy-6-quinolinyl} -4-morpholino-
[612] (2.07 mmol) of trimethylsilyl 4-bromo-but-2-enoate, 8 mL of methylene chloride, 270 μL (3.10 mmol) of oxalyl chloride and 2 drops of DMF were mixed to obtain 5-bromo- 0.0 &gt; mmol &lt; / RTI &gt; After the bubbling settling, the solvent is stripped and then dissolved in 10 mL of THF. 6-amino of the acid chloride solution was cooled under N ₂ to 0 ℃ -4 - [(3- bromo-4-fluorophenyl) amino] -7-methoxy-quinoline-3-carbonitrile 800mg (2.07mmol), 50 mL of THF and 721 [mu] L (4.14 mmol) of N, N-diisopropylethylamine. At 1.5 hours, the mixture is added to a solution of 900 mu L (10.4 mmol) morpholine in 4.3 mL THF at 0 &lt; 0 &gt; C. After fully adding, the temperature is raised to 25 ° C, and then 900 μl or more of morpholine is added at 2 hours. After 3 hours, it is poured into a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, dried with sodium sulfate, and the solvent is reduced slightly. The compound was loaded onto a silica gel column and eluted with 12% methanol / ethyl acetate, then the solvent was stripped from the desired fractions and dried under vacuum to give 287 mg of an orangeish brown solid: mass spectrum (electrospray, m / e): M + H 539.9, 541.9.
[613] Example 176
[614] 4 - [(3-bromophenyl) amino] -7-ethoxy-6-methoxy-3-quinolinecarbonitrile
[615] A mixture of 500 mg (1.90 mmol) of 4-chloro-7-ethoxy-6-methoxy-3-quinolinecarbonitrile, 20 mL of ethanol and 250 μL (2.28 mmol) of 3-bromoaniline was heated to reflux under N ₂ . At the third hour, 103 mu L (0.95 mmol) of ethanol and 10 mL of ethanol are added and the mixture is refluxed overnight. Heat is removed and then made basic with saturated sodium bicarbonate. The solvent is stripped, the residue is slurried with hexane and the solids are collected and dried. Wash with water and dry under vacuum to give 554 mg of a tan solid: Mass spectrum (electrospray, m / e): M + H = 398, 399.8.
[616] Example 177
[617] 4-r (3-hydroxy-4-methylphenyl) amino] -6-methoxy-3-quinolinecarbonitrile
[618] By heating a mixture of the 4-chloro-7-ethoxy-6-methoxy-quinoline-3-carbonitrile 500mg (1.90mmol), 30mL ethanol, and 3-hydroxy-4-methylaniline 281mg (2.28mmol) under N ₂ Reflux. Heat is removed and then made basic with saturated sodium bicarbonate. The solvent is stripped off and the residue is slurried with hexane. The solid was collected, washed with water and then dried under vacuum to give 364 mg of an off-white solid: Mass spectrum (electrospray, m / e): M + H = 349.9.
[619] Example 178
[620] 4-chloro-7-ethoxy-6-methoxy-3-quinolinecarbonitrile
[621] 122 mg (0.50 mmol) of 7-ethoxy-1,4-dihydro-6-methoxy-4-oxo-3-quinolinecarbonitrile and 2.0 mL of methylene chloride were mixed under N ₂ , . 218 [mu] l (2.5 mmol) of oxalyl chloride and 10 [mu] l (0.125 mmol) of DMF are added. It is stirred overnight, diluted with chloroform, and then stirred with saturated sodium bicarbonate until basic. The layers were separated and the organics were dried with magnesium sulfate and the solvent was stripped and dried under vacuum to give 117 mg of a tan solid: Mass spectrum (electrospray, m / e): M + H 262.8, 264.8.
[622] Example 179
[623] Ethoxy-1,4-dihydro-6-methoxy-4-oxo-3-quinolinecarbonitrile
[624] It was added n- butyllithium 54.0mL (135mmol) in 150mL THF and cooled to -78 ℃ under N _2. 7.05 mL (135 mmol) of acetonitrile in 200 mL of THF is added dropwise over 20 minutes. After stirring for 15 minutes, a solution of 17.99 g (64.2 mmol) of 4-ethoxy-5-methoxy-2- (dimethylaminomethyleneamino) benzoate in 150 mL of THF is added dropwise over 20 minutes. Stir at -78 ° C for 0.5 hour. 11.0 mL (193 mmol) of acetic acid was added, and then the temperature was gradually raised to 25 占 폚. After 2.5 hours, the solvent was stripped and the residue was slurried with water, then the solid was collected and dried under vacuum to give 13.025 g of a yellow solid: Mass spectrum (electrospray, m / e): M + H 245.2.
[625] Example 180
[626] Methyl 4-ethoxy-5-methoxy-2- (dimethylaminomethyleneamino) benzoate
[627] Heat the mixture of the methyl 2-amino-4-ethoxy-5-methoxy benzoate 15.056g (66.9mmol) and N, N- dimethylformamide dimethylacetal 14.1mL (100mmol) in 100 ℃ under N _2. After 4.5 hours, add 4.7 mL (33.3 mmol) of DMF / DMA and remove the heat at 5 hours. The solvent was stripped, azeotroped with toluene and then dried under vacuum to give 18.211 g of a dark brown solid: Mass spectrum (electrospray, m / e): M + H 281.3.
[628] Example 181
[629] Methyl 2-amino-4-ethoxy-5-methoxybenzoate
[630] Methyl 4-ethoxy-5-methoxy-2-nitrobenzoate 24.110g (94.5mmol), iron powder, 15.81g (283mmol), ammonium chloride 25.28g (472mmol), a mixture of 135mL water and 350mL of methanol under N ₂ And heated to reflux. Add the same amount of iron and ammonium chloride to both the third hour and the fifth hour. Heat is removed at 6.5 hours, ethyl acetate and saturated sodium bicarbonate are added, then filtered through celite and the layers are separated. The organic layer was washed with saturated sodium bicarbonate, dried over magnesium sulfate, and the solvent was stripped and dried under vacuum to give 17.594 g of a pink solid: Mass spectrum (electrospray, m / e): M + H 226.2 .
[631] Example 182
[632] Methyl 4-ethoxy-5-methoxy-2-nitrobenzoate
[633] 5.00 g (23.7 mmol) of methyl 4-ethoxy-3-methoxybenzoate are dissolved in 25 ml of acetic acid under N ₂ , and 6.1 ml (95.1 mmol) of 69% nitric acid is added dropwise over 30 minutes. Heat at 50 ° C for 1.5 hours, then pour into an ice bath. Extracted with chloroform, washed with dilute sodium hydroxide, and then filtered through magnesium sulfate. The solvent was stripped and dried under vacuum to afford 5.268 g of an off-white solid: Mass spectrum (electrospray, m / e): M + H 255.8.
[634] Example 183
[635] Methyl 4-ethoxy-3-methoxybenzoate
[636] Banil methyl acrylate 25.0g (137mmol), heat the mixture of potassium carbonate and 38.87g (274mmol), DMF 500mL ethyl iodide and 16.5mL (206mmol) in 100 ℃ under N _2. After cooling for 2.5 hours, the solid is removed. The solvent is stripped off and partitioned between water and methylene chloride. The solvent was stripped and dried in vacuo to give 25.85 g of a white solid: Mass spectrum (EI, m / e): M = 210.0.
[637] Example 184
[638] Quinolinyl] -4-dimethylamino- (Z) -2-butenamide &lt; / RTI &gt;
[639] (0.118 mmol) of N-4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl] The mixture with 6 mg of Lindlar catalyst is hydrogenated at room temperature overnight. The mixture is filtered through a pad of celite. After removal of the solvent, the residue is purified by thin layer chromatography eluting with 30% methanol in ethyl acetate. The product was dried to give 0.018 g (36%) of light yellow solid: HRMS m / z 423.1270 (M ⁺ ).
[640] Example 185
[641] Quinolinyl] -4-methoxy- (Z) -2-butenamide &lt; / RTI &gt;
[642] (0.118 mmol) of N- [4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl] And 6 mg of Linndler catalyst is hydrogenated at room temperature for 5.5 hours. The mixture is filtered through a pad of celite. Solvent was removed to give 0.05 g (99.7%) of a yellow solid: HRMS m / z 410.0928 (M ⁺ .
[643] Example 186
[644] Amino] -3-cyano-6-quinolinyl] amino] -2-methylene-4-oxo-butanoic acid
[645] And [(3-bromophenyl) amino] quinoline-3-carbonitrile in the partitioned Nitrile 0.1g (0.30mmol) solution - itaconic anhydride (0.14g, 1.25mmol) with 2mL of ethyl acetate under N ₂ of 6- amino-4 . After stirring overnight at room temperature, the reaction solution is added to ice water and hexane. The product was collected and washed with water, ether and hexane and then dried under vacuum to afford 0.09 g (68%) of a yellowish brown solid: ESMS m / z 451.2 (M + H ⁺ ).
[646] Example 187
[647] N- [4- [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-diethylamino-2-butynamide
[648] Isobutyl chloroformate (0.261g, 1.91mmol) under a N ₂ tetrahydrofuran 50mL solution of 4-diethylamino-2-butyric acid (0.456g, 2.94mmol) and N- methylmorpholine (0.294g, 2.94mmol ) &Lt; / RTI &gt; After stirring for 30 min, a solution of 0.5 g (1.47 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile in 3 mL of pyridine was added dropwise, Lt; / RTI &gt; The reaction is quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and then purified by thin layer chromatography eluting with 15% methanol in ethyl acetate. The product was collected and dried in vacuo to give 0.2 g (28.5%) of a pale yellowish solid (mp: 133-135 占 폚); ESMS m / z 476.2, 478.2 (M + H ^& lt ^{; +} & gt ^; ).
[649] Example 188
[650] Amino] -3-cyano-6-quinolinyl] -4- (N-ethylpiperazino) -2-butynamide
[651] Isobutyl chloroformate (0.785g, 5.75mmol) in 50mL of tetrahydrofuran 4- (N- ethyl-piperazino) -2-butynyl acid (1.75g, 8.85mmol) and N- methyl morpholine under N ₂ ( 1.3453 g, 13.3 mmol). After stirring for 30 minutes, a solution of 1.5 g (4.42 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile in 10 mL of pyridine was added dropwise, Lt; / RTI &gt; The reaction is quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer is concentrated and then purified by flash column chromatography. The product fractions were collected and dried under vacuum to give 1.07 g (46%) of a pale brown solid (mp: 161 캜) (decomp.); ESMS m / z 517.1, 519.1 (M + H ^& lt ^{; +} & gt ^; ).
[652] Example 189
[653] Amino-3-cyano-6-quinolinyl] -4-diethylamino-2-butynamide
[654] Isobutyl chloroformate (0.061g, 0.448mmol) under a N ₂ tetrahydrofuran 10mL solution of 4-diethylamino-2-butyric acid (0.104g, 0.672mmol) and N- methylmorpholine (0.068g, 0.672mmol ) Add ice to ice cold solution. After stirring for 30 minutes, a solution of 0.1 g (0.32 mmol) of 6-amino-4 - [(3-chloro-4- fluorophenyl) amino] -3-quinolinecarbonitrile in 1.5 mL of pyridine was added dropwise, Is stirred at 0 &lt; 0 &gt; C for 1.5 hours. The reaction is quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and then purified by thin layer chromatography eluting with 15% methanol in ethyl acetate. The product was collected and dried under vacuum to give 0.046 g (32%) of a light brown solid (mp: 117-120 ° C); ESMS m / z 450.2 (M + H ^& lt ^{; +} & gt ^; ).
[655] Example 190
[656] Amino] -3-cyano-6-quinolinyl] -4- (N-methylpiperazino) -2-butynamide
[657] Isobutyl chloroformate (0.785g, 5.75mmol) in 10mL of tetrahydrofuran 4- (N- methyl-piperazino) -2-butynyl acid (1.65g, 8.85mmol) and N- methyl morpholine under N ₂ ( 1.36 g, 13.3 mmol). After stirring for 30 minutes, a solution of 1.5 g (4.42 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile in 10 mL of pyridine was added dropwise, Lt; / RTI &gt; The reaction is quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and then purified by thin layer chromatography eluting with 15% methanol in ethyl acetate. The product was collected and dried under vacuum to give 0.37 g (16%) of a yellow solid (mp: 190 캜) (decomp.); ESMS m / z 503,505 (M + H ^& lt ^{; +} & gt ^; ).
[658] Example 191
[659] Amino] -3-cyano-6-quinolinyl] -4- (N-isopropyl-N-methylamino) -2-butynamide
[660] Isobutyl chloroformate (0.785g, 5.75mmol) under N ₂ in the 4-tetrahydrofuran 80mL (N- isopropyl -N- methylamino) -2-butyric acid (1.4g, 8.84mmol) and N- methyl Morpholine (0.94 g, 9.3 mmol) was added dropwise to the ice bath. After stirring for 30 minutes, a solution of 1.5 g (4.42 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile in 15 mL of pyridine was added dropwise, Lt; / RTI &gt; The reaction is quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer is concentrated and then purified by flash column chromatography. The product fractions were collected and dried under vacuum to give 0.65 g (31%) of a reddish brown solid (mp: 124-126 DEG C); ESMS m / z 476.0, 478.0 (M + H ^& lt ^{; +} & gt ^; ).
[661] Example 192
[662] N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-diisopropylamino-
[663] Isobutyl chloroformate (0.785 g, 5.75 mmol) was added under N ₂ to a solution of 4-diisopropylamino-2-butynoic acid (1.65 g, 8.85 mmol) and N- methylmorpholine (0.94 g, 9.3 mmol) in 100 mL of tetrahydrofuran mmol) &lt; / RTI &gt; After stirring for 30 minutes, a solution of 1.5 g (4.42 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile in 15 mL of pyridine was added dropwise, Lt; / RTI &gt; The reaction is quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer is concentrated and then purified by flash column chromatography. The product fractions were collected and dried under vacuum to give 1.08 g (48%) of a pale brown solid (mp: 130 캜) (decomp.); ESMS m / z 504.1, 506.1 (M + H ^& lt ^{; +} & gt ^; ).
[664] Example 193
[665] Amino-3-cyano-6-quinolinyl] -4-dimethylamino-2-butynamide
[666] (1.85 g, 14.4 mmol) and N-methylmorpholine (1.5 g, 14.8 mmol) in 100 mL of tetrahydrofuran under N _{2 were} added isobutyl chloroformate (0.85 g, 6.2 mmol) Add ice to ice cold solution. After stirring for 30 minutes, a solution of 1.5 g (4.79 mmol) of 6-amino-4 - [(3-chloro-4- fluorophenyl) amino] -3-quinolinecarbonitrile in 15 mL of pyridine was added dropwise, 0.0 &gt; 0 C &lt; / RTI &gt; for 2 hours. The reaction is quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer is concentrated and then purified by flash column chromatography. The product fractions were collected and dried under vacuum to give 0.47 g (23%) of a reddish brown solid (mp: 225 캜) (decomp.); ESMS m / z 422.0 (M + H ^& lt ^{; +} & gt ^; ).
[667] Example 194
[668] Amino] -3-cyano-6-quinolinyl] -4-methoxy-2-butynamide
[669] Isobutyl chloroformate (0.85g, 6.2mmol) in 100mL of tetrahydrofuran and 4-methoxy-2-butyric acid under N ₂ (1.1g, 9.6mmol) and N- methylmorpholine (1.02g, 10mmol) ice Add it to cold water. After stirring for 30 minutes, a solution of 1.5 g (4.79 mmol) of 6-amino-4 - [(3-chloro-4- fluorophenyl) amino] -3-quinolinecarbonitrile in 15 mL of pyridine was added dropwise, Stir at 0 ° C for 3 hours. The reaction is quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer is concentrated and then purified by flash column chromatography. The product fractions were collected and dried under vacuum to give 0.73 g (37%) of a pale yellowish brown solid (mp: 170-171 C); ESMS m / z 409 (M + H ^& lt ^{; +} & gt ^; ).
[670] Example 195
[671] 4 - [(3-bromo-4-fluorophenyl) amino] -6-nitro-3-quinolinecarbonitrile
[672] A mixture of 3.8 g (16.33 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile and 3.7 g (20 mmol) of 3-bromo-4-fluoroaniline in 200 mL of ethanol is refluxed for 3 hours. After removal of the solvent, the residue is dissolved in ethyl acetate and washed with sodium bicarbonate. 6.5 g (71%) of the product as a pale yellow solid (mp: 269-270 ° C) (decomp.): ESMS m / z 387.3, 389.2.
[673] Example 196
[674] 6-Amino-4 - [(3-bromo-4-fluorophenyl) amino] -3-quinolinecarbonitrile
[675] (20.67 mmol) of 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-3-quinolinecarbonitrile, 4 g (72.35 mmol) of iron dust in 240 mL of methanol and water (2: And 8.9 g (165.36 mmol) of ammonium chloride is refluxed for 4 hours. The mixture is filtered hot, then washed with methanol and water. The product precipitates from the filtrate upon cooling. The solid was collected and dried in vacuo to give 5.8 g (79%) of a yellowish brown solid (mp: 210-212 ° C): ESMS m / z 356.8, 358.8.
[676] Example 197
[677] N- [4 - [(3-bromo-4-fluorophenyl) amino] -3-cyano-6- quinolinyl]
[678] Isobutyl chloroformate (0.373g, 2.73mmol) under a N ₂ tetrahydrofuran 80mL solution of 4-dimethylamino-2-butyric acid (0.8g, 6.3mmol) and N- methylmorpholine (0.658g, 6.5mmol) Add ice to ice cold solution. After stirring for 30 minutes, a solution of 10.65 g (2.1 mmol) of 6-amino-4 - [(3-bromo-4- fluorophenyl) amino] -3-quinolinecarbonitrile in 10 mL of pyridine was added dropwise, Is stirred at 0 &lt; 0 &gt; C for 2.5 hours. The reaction is quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer is concentrated and then purified by flash column chromatography. The product fractions were collected and dried under vacuum to give 0.33 g (33%) of a yellow solid (mp: 228-231 [deg.] C); ESMS m / z 465.9, 467.9 (M + H) &lt; ⁺ & gt ^; .
[679] Example 198
[680] 2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-7-methoxy-quinolin-
[681] (5.1 mmol) of 4 - [(3-bromophenyl) amino] -7-methoxy-6-amino-3-quinolinecarbonitrile and 5.3 mL (31 mmol) of Hunig's base in 110 mL of anhydrous THF In THF is added a solution of THF containing 5.7 g (31 mmol) of 4-bromocrotonyl chloride at 0 &lt; 0 &gt; C with stirring. The mixture is stirred for an additional 0.5 h after addition. 100 mL of saturated sodium chloride solution is added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate solution is dried over sodium sulfate and then added dropwise to 40 mL of a dimethylamine solution (2.0 M in THF) at 0 ° C. The solution is stirred for an additional 0.5 h. The mixture is poured into dilute sodium bicarbonate. The organic layer is separated and dried with sodium sulfate. Chromatograph gave 1.4 g of a beige solid: mass spectrum (electrospray, m / e): M + H 480.0, 481.9.
[682] Example 199
[683] Diethylamino-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-7-methoxy-quinolin-
[684] A mixture of 0.5 g (1.36 mmol) of 4 - [(3-bromophenyl) amino] -7-methoxy-6-amino-3-quinolinecarbonitrile in 50 mL of dry THF and 0.48 mL (2.7 mmol) Is stirred at 0 &lt; 0 &gt; C in THF solution containing 0.50 g (2.7 mmol) of 4-bromocrotonyl chloride. The mixture is stirred for an additional 0.5 h after addition and then added dropwise to a solution of 4.2 mL (40.8 mmol) of diethylamine in 50 mL of THF at 0 &lt; 0 &gt; C. The solution is stirred for an additional 0.5 h. The mixture is poured into dilute sodium bicarbonate solution. The organic layer is separated and dried with sodium sulfate. Chromatograph gave 0.2 g of white solid: mass spectrum (electrospray, m / e): M + H 508.1, 510.8.
[685] Example 200
[686] Synthesis of 4-morpholin-4-yl-but-2-enoic acid [4- (3-bromo-phenylamino) -3- cyano-7-methoxy-quinolin-
[687] A mixture of 0.69 g (1.87 mmol) of 4 - [(3-bromophenyl) amino] -7-methoxy-6-amino-3-quinolinecarbonitrile and 0.98 mL (5.6 mmol) of Hunig's base in 50 mL of dry THF Is added dropwise with stirring at 0 &lt; 0 &gt; C a THF solution containing 0.86 g (5 mmol) of 4-bromocrotonyl chloride. The mixture is stirred for an additional 0.5 h and then added to a solution of 4.89 mL (56 mmol) of morpholine in 50 mL of THF at 0 &lt; 0 &gt; C. The solution is stirred for an additional 0.5 h, then the mixture is poured into dilute sodium bicarbonate solution. The organic layer is separated and dried with sodium sulfate. The residue was chromatographed to give 0.38 g of a gray solid: Mass spectrum (electrospray, m / e): M + H 521.9, 523.8.
[688] Example 201
[689] 4- (3-Chloro-4-fluoro-phenylamino) -7-methoxy-6-nitro-quinoline-
[690] A mixture of 4.4 g (16.7 mmol) of 4-chloro-7-methoxy-6-nitro-3-quinolinecarbonitrile and 2.67 g (18.3 mmol) of 3-chloro-4-fluoroaniline in 110 ml of methoxyethanol was treated with nitrogen Lt; / RTI &gt; for 4 hours. The reaction mixture is diluted with ethyl acetate and washed with sodium bicarbonate solution and sodium chloride solution. The organic layer is dried over sodium sulfate and the solvent is removed in vacuo. The residue was chromatographed on silica gel, eluting with a mixture of ethyl acetate and methanol, to give 3 g of a yellow solid: mass spectrum (electrospray, m / e): 372.9.
[691] Example 202
[692] 6- amino-4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-quinoline-
[693] 4.88 g (13 mmol) of 4 - [(3-chloro-4-fluorophenyl) amino] -7-methoxy-6-nitro- quinoline- (58.5 mmol) is stirred under reflux for 4.5 hours in 60 mL water and 60 mL methanol. The mixture is diluted with 500 mL of hot ethyl acetate and the hot mixture is filtered. The filtrate is washed with saturated sodium bicarbonate solution and the organic layer is dried over sodium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and methanol to give 3.38 g of a yellow solid: Mass spectrum (electrospray, m / e): M + H 343.4.
[694] Example 203
[695] Chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide
[696] (3.1 mmol) of 4 - [(3-chloro-4-fluorophenyl) amino] -7-methoxy-6-amino- quinoline-3-carbonitrile in 30 mL of dry THF and 1.7 mL mmol) is added to a THF solution containing 1.99 g (9.3 mmol) of 4-bromocrotonyl chloride at 0 &lt; 0 &gt; C with stirring. The mixture is stirred at 0 &lt; 0 &gt; C under nitrogen for a further 0.5 h. 50 mL of a saturated sodium chloride solution is added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate solution is separated, dried over sodium sulfate and then added dropwise to 31 mL of a dimethylamine solution (2.0 M in THF) at 0 ° C. After the addition, the solution is stirred at room temperature for an additional hour. The mixture is poured into dilute sodium bicarbonate solution. The organic layer was separated and the residue was chromatographed to give 0.86 g of a white solid: Mass spectrum (electrospray, m / e): &lt; RTI ID =
[697] Example 204
[698] Chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide
[699] (3.2 mmol) of 4 - [(3-chloro-4-fluorophenyl) amino] -7-methoxy-6-amino- quinolinecarbonitrile in 40 mL of anhydrous THF, 2.24 mL (12.8 mmol) Is added a THF solution containing 2.34 g (12.8 mmol) of 4-bromocrotonyl chloride at 0 &lt; 0 &gt; C with stirring. The mixture is stirred at 0 &lt; 0 &gt; C for an additional 0.5 h. 50 mL of a saturated sodium chloride solution is added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate solution is dried over sodium sulfate and then added dropwise to a solution of 6.6 mL (64 mmol) of diethylamine in 5 mL of THF at 0 &lt; 0 &gt; C. The solution is stirred at 0 &lt; 0 &gt; C for an additional hour. The mixture is poured into dilute sodium bicarbonate solution. The organic layer is separated and dried with sodium sulfate. The residue was chromatographed and recrystallized to give 0.62 g of a white solid: Mass spectrum (electrospray, m / e): M + H 482.0.
[700] Example 205
[701] Chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide
[702] (3.5 mmol) of 4 - [(3-chloro-4-fluorophenyl) amino] -7-methoxy-6-amino- quinoline- ) Was added dropwise to a THF solution containing 2.57 g (14 mmol) of 4-bromocrotonyl chloride with stirring at 0 ° C. The mixture is stirred at 0 &lt; 0 &gt; C for an additional hour. 50 mL of a saturated sodium chloride solution is added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate solution is dried over sodium sulphate and then added to a solution of 4.58 mL (52.5 mmol) morpholine in 5 mL THF at 0 &lt; 0 &gt; C. The solution is stirred at O &lt; 0 &gt; C overnight. The mixture is poured into dilute sodium bicarbonate solution. The organic layer is dried with sodium sulfate. Chromatograph gave 0.83 g of an off-white solid: Mass spectrum (electrospray, m / e): M + H 496.0.
[703] Example 206
[704] 4- (3-Bromo-4-fluoro-phenylamino) -7-methoxy-6-nitro-quinoline-
[705] A mixture of 3.52 g (9.7 mmol) of 4-chloro-7-methoxy-6-nitro-3-quinolinecarbonitrile and 2.0 g (10.7 mmol) of 3-bromo-4-fluoroaniline in 150 ml of methoxyethanol And refluxed under nitrogen for 5.5 hours. The reaction mixture is diluted with ethyl acetate and washed with sodium bicarbonate solution and sodium chloride solution. The organic layer is dried over sodium sulfate and the solvent is removed in vacuo. The residue was chromatographed on silica gel, eluting with a mixture of ethyl acetate and methanol, to give 3 g of a yellow solid: mass spectrum (electrospray, m / e): 416.8, 418.8.
[706] Example 207
[707] 6- amino-4- (3-bromo-4-fluoro-phenylamino) -7-methoxy-quinoline-
[708] 2.9 g (6.95 mmol) of ammonium chloride, 6.5 g (121.6 mmol) of ammonium chloride, and 2.9 g (6.6 mmol) of ammonium chloride were added to a solution of 4 - [(3-bromo-4-fluorophenyl) amino] -7- (73mmol) is stirred for 6 hours in 50mL water and 50mL methanol. The mixture is diluted with hot ethyl acetate and the hot mixture is filtered. The filtrate is washed with a saturated sodium chloride solution and the organic layer is dried over sodium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and methanol to give 2.11 g of a light yellow solid: Mass spectrum (electrospray, m / e): M + H 386.7, 388.8 .
[709] Example 208
[710] 4-Dimethylamino-but-2-enoic acid [4- (3-bromo-4-fluoro-phenylamino) -3- cyano-7-methoxy-quinolin-
[711] (1.98 mmol) of 4 - [(3-bromo-4-fluorophenyl) amino] -7-methoxy-6-amino- quinoline-3-carbonitrile in 3.5 mL of anhydrous THF and 3.5 mL 20 mmol) was added dropwise with stirring at 0 &lt; 0 &gt; C a THF solution containing 2.2 g (12 mmol) of 4-bromocrotonyl chloride. The mixture is stirred at 0 &lt; 0 &gt; C for a further 30 minutes. 50 mL of a saturated sodium chloride solution is added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and then added dropwise to 15 mL (2.0 M) of dimethylamine at 0 ° C. The solution is stirred at room temperature for an additional hour. The mixture is poured into dilute sodium bicarbonate solution. The organic layer is dried over sodium sulfate and the solvent is removed in vacuo. The residue was chromatographed to give 0.55 g of a beige solid: Mass spectrum (electrospray, m / e): M + H 498.0, 500.0.
[712] Example 209
[713] 2-enoic acid [4- (3-bromo-4-fluoro-phenylamino) -3-cyano-
[714] (1.98 mmol) of 4 - [(3-bromo-4-fluorophenyl) amino] -7-methoxy-6-amino- quinoline-3-carbonitrile in 3.5 mL of anhydrous THF and 3.5 mL 20 mmol) was added dropwise with stirring at 0 &lt; 0 &gt; C a THF solution containing 2.2 g (12 mmol) of 4-bromocrotonyl chloride. The mixture is stirred at 0 &lt; 0 &gt; C for a further 30 minutes. 50 mL of NaCl saturated solution is added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate solution is dried over sodium sulfate and then added dropwise to a solution of 3.1 mL (30 mmol) of diethylamine in 5 mL of THF at 0 ° C. The solution is stirred at 0 &lt; 0 &gt; C for an additional hour and then at room temperature for 30 minutes. The mixture is poured into dilute sodium bicarbonate solution. The organic layer is dried over sodium sulfate and the solvent is removed in vacuo. Chromatography of the residue gave 0.4 g of an off-white solid: Mass spectrum (electrospray, m / e): M + H 525.9, 527.9.
[715] Example 210
[716] 7-Ethoxy-4-hydroxy-quinoline-3-carbonitrile
[717] A mixture of 10 g (73 mmol) of 3-ethoxy aniline and 12.3 g (73 mmol) of ethyl (ethoxymethylene) cyanoacetate is heated in 90 ml of doughethm at 140 ° C for 7 hours. To the mixture is added 250 mL of Dawsam. The solution is stirred and then the removed ethanol is refluxed under nitrogen for 12 hours with periodic distillation. The mixture is cooled to room temperature and the solid is collected and washed with hexane. The crude solid was treated with boiling ethanol and filtered to give 9.86 g of a brown solid: Mass spectrum (electrospray, m / e): M + H 214.7.
[718] Example 211
[719] 7-Ethoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile
[720] To a suspension of 5 g (23 mmol) of 7-ethoxy-4-hydroxy-quinoline-3-carbonitrile in 75 mL of trifluoroacetic anhydride was added 5.5 g (69 mmol) of ammonium nitrate over 6 hours at room temperature. The excess anhydride is removed at 45 [deg.] C under reduced pressure. The residue is stirred with 300 mL of water. The solid was collected and treated with boiling ethanol to give 3.68 g of a tan solid: Mass spectrum (electrospray, m / e): M + H 259.8.
[721] Example 212
[722] Chloro-7-ethoxy-6-nitro-quinoline-3-carbonitrile
[723] A mixture of 3.45 g (13 mmol) of 7-ethoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile, 5.55 g (26 mmol) of contamination and 10 mL of phosphorus oxychloride is refluxed for 3 hours. The mixture is diluted with hexane and the solids are collected. The solid is dissolved in 500 mL of ethyl acetate and washed with cold dilute sodium hydroxide solution. The solution is dried over magnesium sulfate and filtered through a pad of silica gel. Removal of the solvent gave 2.1 g of a beige solid: Mass spectrum (electrospray, m / e): M + H 277.7.
[724] Example 213
[725] 4- (3-Bromo-phenylamino) -7-ethoxy-6-nitro-quinoline-
[726] A mixture of 2.1 g (7.6 mmol) of 4-chloro-7-ethoxy-6-nitro-3-quinolinecarbonitrile and 0.91 mL (8.3 mmol) of 3-bromoaniline in 100 mL of ethanol is refluxed under nitrogen for 4.5 hours . The reaction mixture is poured into dilute sodium bicarbonate solution. Remove the ethanol under vacuum. The mixture is diluted with diluted ethyl acetate, the organic layer is separated and dried over sodium sulfate. The solution is concentrated, the solid is collected and washed with hexane. Upon drying, 2.6 g of a yellow solid are obtained: Mass spectrum (electrospray, m / e): M + H 412.8, 414.9.
[727] Example 214
[728] 6-Amino-4- (3-bromo-phenylamino) -7-ethoxy-quinoline-
[729] A mixture of 2.5 g (6 mmol) of 4 - [(3-bromophenyl) amino] -7-ethoxy-6-nitro- quinoline- Is stirred for 4 hours in 40 mL water and 40 mL methanol. The mixture is diluted with hot ethyl acetate to 500 mL and the hot mixture is filtered. The filtrate is washed with a saturated sodium chloride solution and the organic layer is dried over sodium sulfate. The solution was concentrated to give 1.5 g of a beige solid: Mass spectrum (electrospray, m / e): M + H 382.8, 384.8.
[730] Example 215
[731] 2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-7-ethoxy-quinolin-
[732] A mixture of 1.34 g (3.5 mmol) of 4 - [(3-bromo-phenyl) amino] -7-ethoxy-6-amino-3-quinolinecarbonitrile and 3.66 mL (21 mmol) of Hunig's base in 80 mL of dry THF Is added dropwise with stirring at 0 &lt; 0 &gt; C a THF solution containing 3.85 g (21 mmol) of 4-bromocrotonyl chloride. The mixture is stirred at 0 &lt; 0 &gt; C for a further 30 minutes. 50 mL of a saturated sodium chloride solution is added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate solution is dried over sodium sulfate and the desiccant is filtered off. The solution is used without further properties.
[733] Example 216
[734] 2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-7-ethoxy-quinolin-
[735] A 3/1 portion of the solution from Example 18 is added dropwise to 8.75 mL (17.5 mmol) of dimethylamine at 0 &lt; 0 &gt; C. The mixture is stirred at 0 &lt; 0 &gt; C for a further 30 minutes. The mixture is diluted with sodium bicarbonate solution, the organic layer is separated and dried. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and methanol to give 0.32 g of a beige solid: Mass spectrum (electrospray, m / e): M + H 494.0, 496.0.
[736] Example 217
[737] Diethylamino-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-7-ethoxy-quinolin-
[738] A 3/1 portion of the solution from Example 18 is added dropwise at 0 &lt; 0 &gt; C to a solution of 1.81 mL (17.5 mmol) of diethylamine in 5 mL of THF. The mixture is stirred at 0 &lt; 0 &gt; C for a further 30 minutes. The mixture is diluted with sodium bicarbonate solution, the organic layer is separated and dried. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and methanol to give 0.22 g of a beige solid: Mass spectrum (electrospray, m / e): M + H 522.0, 524.0.
[739] Example 218
[740] Synthesis of 4-morpholin-4-yl-but-2-enoic acid [4- (3-bromo-phenylamino) -3- cyano-7-ethoxy-quinolin-
[741] A 3/1 portion of the solution from Example 18 is added dropwise at 0 &lt; 0 &gt; C to a solution of 1.57 mL (18 mmol) morpholine in 5 mL THF. The mixture is stirred at 0 &lt; 0 &gt; C for a further 30 minutes. The mixture is diluted with sodium bicarbonate solution, the organic layer is separated and dried. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and methanol to give 0.37 g of white solid: Mass spectrum (electrospray, m / e): M + H 535.9 , 538.0.
[742] Example 219
[743] 8-Methoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile
[744] A mixture of 12.6 g (75 mmol) of 2-methoxy-4-nitroaniline and 12.7 g (75 mmol) of ethyl (ethoxymethylene) cyanoacetate was heated in 100 mL of dasom at night overnight at 120 &Lt; / RTI &gt; 300 mL of Dawsome is added to the mixture. The solution is stirred and then the removed ethanol is refluxed under nitrogen for 12 hours with periodic distillation. The mixture is cooled to room temperature and the solid is collected and washed with hexane. The crude solid was treated with boiling ethanol and then filtered to give 12 g of a brown solid: Mass spectrum (electrospray, m / e): M + H 245.8.
[745] Example 220
[746] 4-Chloro-8-methoxy-6-nitro-quinoline-3-carbonitrile
[747] A mixture of 4 g (16 mmol) of 8-methoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile, 6.66 g (32 mmol) of contamination and 15 mL of phosphorus oxychloride is refluxed for 2.5 hours. The mixture is diluted with hexane and the solids are collected. The solid is dissolved in 500 mL of ethyl acetate and washed with cold dilute sodium hydroxide solution. The solution is dried over magnesium sulfate and filtered through a pad of silica gel. Removal of the solvent gave 2.05 g of a tan solid: Mass spectrum (electrospray, m / e): M + H 263.7.
[748] Example 221
[749] Nitro-4- (3-bromo-phenylamino) -8-methoxy-quinoline-3-carbonitrile
[750] A mixture of 1.9 g (7.6 mmol) of 4-chloro-8-methoxy-6-nitro-quinoline-3-carbonitrile and 0.86 mL (8.3 mmol) of 3-bromoaniline in 95 mL of ethanol was refluxed . The reaction mixture is poured into dilute sodium bicarbonate solution. Remove the ethanol under vacuum. The mixture is diluted with ethyl acetate, the organic layer is separated and dried over sodium chloride. The solution is concentrated, the solid is collected and washed with hexane. Upon drying, 2.3 g of a yellow solid are obtained: Mass spectrum (electrospray, m / e): M + H 398.8, 400.8.
[751] Example 222
[752] 6-Amino-4- (3-bromo-phenylamino) -8-methoxy-quinoline-
[753] 2.15 g (5 mmol) of 4 - [(3-bromophenyl) amino] -8-methoxy-6-nitro- Is stirred for 3 hours in 40 mL water and 40 mL methanol. The mixture is diluted with hot ethyl acetate to 500 mL and the hot mixture is filtered. The filtrate is washed with a saturated sodium chloride solution and the organic layer is dried over sodium sulfate. The solution was concentrated to give 0.43 g of a violet solid: mass spectrum (electrospray, m / e): M + H 368.9, 370.9.
[754] Example 223
[755] 2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-8-methoxy-quinolin-
[756] To a solution of 1.05 g (2.8 mmol) of 4 - [(3-bromo-phenyl) amino] -8-methoxy-6-amino-3-quinolinecarbonitrile and 3.9 mL (22.4 mmol) of Hunig's base in 50 mL of dry THF To the mixture is added a THF solution containing 4.11 g (22.4 mmol) of 4-bromocrotonyl chloride with stirring at 0 &lt; 0 &gt; C. The mixture is stirred at 0 &lt; 0 &gt; C for a further 1 hour. 50 mL of a saturated sodium chloride solution is added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate solution is dried over sodium sulfate and the desiccant is filtered off. The solution is used without further properties.
[757] Example 224
[758] 4-Dimethylamino-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-8-methoxy-quinolin-
[759] A 3/1 portion of the solution from Example 26 is added dropwise to a solution of 7 mL (14 mmol) of dimethylamine (2.0 M in THF) at 0 ° C. The mixture is stirred at 0 &lt; 0 &gt; C for a further 30 minutes. The mixture is diluted with sodium bicarbonate solution, the organic layer is separated and dried. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and methanol to give 0.22 g of a tan solid: Mass spectrum (electrospray, m / e): M + H 480.0 , 482.0.
[760] Example 225
[761] Amino-3-cyano-8-methoxy-quinolin-6-yl] -amide
[762] A 3/1 portion of the solution from Example 26 is added dropwise at 0 &lt; 0 &gt; C to a solution of 1.4 mL (14 mmol) of diethylamine in 5 mL of THF. The mixture is stirred at 0 &lt; 0 &gt; C for a further 30 minutes. The mixture is diluted with sodium bicarbonate solution, the organic layer is separated and dried. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and methanol to give 95 mg of a tan solid: Mass spectrum (electrospray, m / e): M + H 509.9, 511.0.
[763] Example 226
[764] Yl] -but-2-enoic acid [4- (3-bromo-phenylamino) -3- cyano-8-methoxy-quinolin-
[765] A 3/1 portion of the solution from Example 26 is added dropwise at 0 DEG C to a solution of morpholine (1.2 mL, 14 mmol) in 5 mL of THF. The mixture is stirred at 0 &lt; 0 &gt; C for a further 30 minutes. The mixture is diluted with sodium bicarbonate solution, the organic layer is separated and dried. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and methanol to give 0.21 g of a yellow solid: Mass spectrum (electrospray, m / e): M + H 522.0 , 524.0.
[766] Example 227
[767] 4-Dimethylamino-but-2-enoic acid [4- (3-bromo-phenylamino) -3- cyano-7-methoxy-quinol-
[768] 6.9 mL (5.4 mmol) of isobutyl chloroformate and 1.19 mL (10.8 mmol) of N-methylmorpholine are added dropwise to 1.37 g (10.8 mmol) of 4-dimethylamino-2-butynoic acid in 60 mL of THF on ice. After stirring for 10 minutes, a solution of 1 - (3-bromophenyl) amino] -7-methoxy-6-amino-quinoline-3-carbonitrile in 10 mL of pyridine is introduced. The reaction mixture is stirred overnight at 0 &lt; 0 &gt; C. After evaporation of the solvent, the residue is stirred with dilute sodium bicarbonate. The solution is then extracted with ethyl acetate. The ethyl acetate solution is dried and then removed under vacuum. Chromatograph the residue to obtain 0.18 g of a tan solid; Mass spectrum (electrospray, m / e): 478.0, 480.0.
[769] Example 228
[770] 4- (4-Chloro-2-fluoro-phenylamino) -6,7-dimethoxy-quinoline-
[771] A mixture of 2.0 g 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 1.46 g 4-chloro-2-fluoroaniline, 0.925 g pyridine hydrochloride and 125 mL ethoxyethanol was stirred at reflux temperature Lt; / RTI &gt; The mixture is cooled and then added to 1000 mL of water. The mixture is brought to pH 9 by the addition of sodium carbonate. The product was collected, washed with water and then dried to give 4- (4-chloro-2-fluoro-phenylamino) -6,7-dimethoxy-quinolin- 2.61 g of carbonitrile are obtained; Mass spectrum (electrospray, m / e): 357.9.
[772] Example 229
[773] 4- (3-Hydroxy-4-methyl-phenylamino) -6,7-dimethoxy-quinoline-
[774] A mixture of 2.98 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 1.85 g of 5-amino-o-cresol, 1.39 g of pyridine hydrochloride and 200 mL of ethoxyethanol was stirred at reflux temperature for 1 hour under nitrogen Lt; / RTI &gt; The mixture is cooled and then added to 1000 mL of water. Sodium carbonate is added to the mixture to give a pH of 9. The product was collected, washed with water and then dried to give 4- (3-hydroxy-4-methyl-phenylamino) -6,7-dimethoxy-quinolin- 3.27 g of carbonitrile are obtained; Mass spectrum (EI, m / e): M 335.1269.
[775] Example 230
[776] 4-Hydroxy-6,7,8-trimethoxy-quinoline-3-carbonitrile
[777] A mixture of 4.82 g of methyl 3,4,5-trimethoxy anthranilate in 20 mL of N, N-dimethylformamide dimethylacetal is refluxed for 18 hours and then concentrated in vacuo. The crude amidine product is used in the next step without further purification. At -78 [deg.] C, 17.6 mL of 2.5M n-butyllithium in hexane is added to 25 mL of tetrahydrofuran. Then, 2.35 mL of acetonitrile in 45 mL of tetrahydrofuran is added dropwise. The mixture is stirred at -78 &lt; 0 &gt; C for 15 minutes. Thereafter, a crude amidine solution in 30 mL of tetrahydrofuran is added dropwise. The mixture is stirred at -78 &lt; 0 &gt; C for 30 minutes and then 5.7 ml of acetic acid are added. The mixture is warmed to room temperature and then 100 mL of water is added. The product was collected, washed with water and then dried to give 4.14 g of 4-hydroxy-6,7,8-trimethoxy-quinoline-3-carbonitrile as a solid (mp: 280 캜) (decomposed) ; Mass spectrum (electrospray, m / e): M + H 261.2.
[778] Example 231
[779] 4-Chloro-6,7,8-trimethoxy-quinoline-3-carbonitrile
[780] A mixture of 1.30 g of 4-hydroxy-6,7,8-trimethoxy-quinoline-3-carbonitrile, 10 mL of phosphorus oxychloride and 1 drop of N, N-dimethylformamide was refluxed for 10 minutes and then evaporated Remove volatiles. The residue is stirred with 20 mL of 5% methyl alcohol in acetyl acetate. The product was collected and dried to give 1.12 g of 4-chloro-6,7,8-trimethoxy-quinoline-3-carbonitrile as a solid (mp: 161-163 ° C); Mass spectrum (EI, m / e): M 278.0452.
[781] Example 232
[782] 4- (3-Dimethylamino-phenylamino) -6,7,8-trimethoxy-quinoline-3-carbonitrile
[783] 0.279 g of 4-chloro-6,7,8-trimethoxy-quinoline-3-carbonitrile, 0.23 g of N, N-dimethyl-1,3-phenylenediamine dihydrochloride, 0.2 mL of pyridine and 15 mL of ethoxyethanol Is stirred at reflux temperature under nitrogen for 30 minutes. The mixture is cooled and then added to 100 mL of water. Sodium carbonate is added to the mixture to give a pH of 9. The product was collected, washed with water and then dried to give 4- (3-dimethylamino-phenylamino) -6,7,8-trimethoxy-quinoline-3-carbo 0.251 g of nitrile is obtained; Mass spectrum (EI, m / e): M 378.1685.
[784] Example 233
[785] 4- (3-Hydroxy-4-methyl-phenylamino) -6,7,8-trimethoxy-quinoline-3-carbonitrile
[786] A mixture of 0.279 g of 4-chloro-6,7,8-trimethoxy-quinoline-3-carbonitrile, 0.148 g of 5-amino-ocresol and 10 mL of ethoxyethanol was stirred at reflux temperature for 30 minutes under nitrogen . The mixture is cooled and then added to 100 mL of water. Sodium carbonate is added to the mixture to give a pH of 9. The product was collected, washed with water and then dried to give 4- (3-hydroxy-4-methyl-phenylamino) -6,7,8-trimethoxy- 0.279 g of quinoline-3-carbonitrile are obtained; Mass spectrum (EI, m / e): M 365.1356.
[787] Example 234
[788] 4- (4-Chloro-2-fluoro-phenylamino) -6,7,8-trimethoxy-quinoline-
[789] A mixture of 0.279 g of 4-chloro-6,7,8-trimethoxy-quinoline-3-carbonitrile, 0.177 g of 4-chloro-2-fluoroaniline and 10 mL of ethoxyethanol was stirred at reflux temperature for 30 minutes Lt; / RTI &gt; The mixture is cooled and then added to 100 mL of water. Sodium carbonate is added to the mixture to give a pH of 9. The product is extracted with ethyl acetate, washed with water, dried and concentrated in vacuo. The solid thus obtained is chromatographed over silica gel, eluting with hexane-ethyl acetate from 9: 1 to 2: 1. Solvent was removed from the product fraction to give 4- (4-chloro-2-fluoro-phenylamino) -6,7,8-trimethoxy-quinoline- 0.261 g of 3-carbonitrile are obtained; Mass spectrum (EI, m / e): M 387.0777.
[790] Example 235
[791] 2- (Dimethylamino-methyleneamino) -3,6-dimethoxy-benzoic acid methyl ester
[792] To a solution of 2-amino-3,6-dimethoxybenzoic acid (Manouchehr Azadi-Ardakani and Timothy W. Wallace, Tetrahedron, Vol. 44, No. 18, pp. 5939-5952] is refluxed for 18 hours and then concentrated in vacuo. To the residue is added 180 mL of ethyl acetate. The mixture is filtered, then 200 mL of hexane is added to the filtrate. The mixture is then concentrated to 100 mL. The product was collected and then dried to give 3.25 g of 2- (dimethylamino-methyleneamino) -3,6-dimethoxy-benzoic acid methyl ester as a solid (mp: 81-83 ° C); Mass spectrum (EI, m / e): M 266.1263.
[793] Example 236
[794] 4-Hydroxy-5,8-dimethoxy-quinoline-3-carbonitrile
[795] To 12.5 mL of tetrahydrofuran is added 8.8 mL of 2.5 M n-butyllithium in hexane at -78 <0> C. Then, 1.18 mL of acetonitrile in 25 mL of tetrahydrofuran is added dropwise. The mixture is stirred at -78 &lt; 0 &gt; C for 15 minutes. Then, a solution of 2- (dimethylamino-methyleneamino) -3,6-dimethoxy-benzoic acid methyl ester in 62 mL of tetrahydrofuran is added dropwise. The mixture was stirred at -78 &lt; 0 &gt; C for 10 min and then allowed to warm to room temperature for 15 min. Acetic acid (3 mL) is added followed by 200 mL of water. The product was collected, washed with water and then dried to give 1.57 g of 4-hydroxy-5,8-dimethoxy-quinoline-3-carbonitrile as a solid (mp: 300-330 ° C); Mass spectrum (EI, m / e): M 230.0685.
[796] Example 237
[797] 4-Chloro-5,8-dimethoxy-quinoline-3-carbonitrile
[798] A stirring mixture of 1.30 g of 4-hydroxy-5,8-dimethoxy-quinoline-3-carbonitrile, 10 mL of phosphorus oxychloride and 2 drops of N, N-dimethylformamide was refluxed for 10 minutes, . The residue is stirred with 50 mL of water. The product was collected and dried to give 1.74 g of 4-chloro-5,8-dimethoxy-quinoline-3-carbonitrile as a solid (mp: 165-167 ° C); Mass spectrum (EI, m / e): M 248.0346.
[799] Example 238
[800] 4- (4-Chloro-2-fluoro-phenylamino) -5,8-dimethoxy-quinoline-
[801] A mixture of 0.148 g of 4-chloro-5,8-dimethoxy-3-quinolinecarbonitrile, 0.102 g of 4-chloro-2-fluoroaniline and 5 mL of ethoxyethanol is stirred at reflux temperature for 30 minutes under nitrogen. The mixture is cooled and then added to 50 mL of water. Sodium carbonate is added to the mixture to give a pH of 9. The product was collected and washed with water then dried and washed with 10 mL of hexane-ethyl acetate (4: 1) to give 4- (4-chloro-2-fluoro-phenyl Amino) -5,8-dimethoxy-quinoline-3-carbonitrile; Mass spectrum (EI, m / e): M 329.7609.
[802] Example 239
[803] 4- (3-Hydroxy-4-methyl-phenylamino) -5,8-dimethoxy-quinoline-
[804] A mixture of 0.148 g of 4-chloro-5,8-dimethoxy-3-quinolinecarbonitrile, 0.087 g of 5-amino-oczolone and 5 mL of ethoxyethanol was stirred at reflux temperature for 30 minutes under nitrogen. The mixture is cooled and then added to 50 mL of water. Sodium carbonate is added to the mixture to give a pH of 9. The product was collected and washed with water then dried and washed with 10 mL of hexane-ethyl acetate (4: 1) to give 4- (3-hydroxy-4-methyl-phenyl Amino) -5,8-dimethoxy-quinoline-3-carbonitrile; Mass spectrum (EI, m / e): M 335.1260.
[805] Example 240
[806] 4- (3-Bromo-phenylamino) -5,8-dimethoxy-quinoline-3-carbonitrile
[807] A mixture of 0.148 g of 4-chloro-5,8-dimethoxy-3-quinolinecarbonitrile, 0.12 g of m-bromoaniline and 5 mL of ethoxyethanol was stirred at reflux temperature for 30 minutes under nitrogen. , &Lt; / RTI &gt; Sodium carbonate is added to the mixture to give a pH of 9. The product was collected and washed with water then dried and washed with 10 mL of hexane-ethyl acetate (4: 1) to give 4- (3-bromo-phenylamino) -5 , 8-dimethoxy-quinoline-3-carbonitrile, 0.213g; Mass spectrum (EI, m / e): M 383.0265.
[808] Example 241
[809] 4- (3-Bromo-phenylamino) -6,7,8-trimethoxy-quinoline-3-carbonitrile
[810] A mixture of 0.167 g of 4-chloro-6,7,8-trimethoxy-3-quinolinecarbonitrile, 0.12 g of m-bromoaniline and 5 mL of ethoxyethanol is stirred at reflux temperature for 30 minutes under nitrogen. The mixture is cooled and then added to 50 mL of water. Sodium carbonate is added to the mixture to give a pH of 9. The product was collected and washed with water then dried and washed with 10 mL of hexane-ethyl acetate (4: 1) to give 4- (3-bromo-phenylamino) -6 , 7,8-trimethoxy-quinoline-3-carbonitrile, 0.212 g; Mass spectrum (EI, m / e): M 413.0377.
[811] Example 242
[812] 4- (3-Dimethylamino-phenylamino) -5,8-dimethoxy-quinoline-3-carbonitrile
[813] A mixture of 0.148 g of 4-chloro-5,8-dimethoxy-3-quinolinecarbonitrile, 0.146 g of N, N-dimethyl-1,3-phenylenediamine dihydrochloride, 0.2 mL of pyridine and 5 mL of ethoxyethanol was purged with nitrogen &Lt; / RTI &gt; at reflux temperature for 30 minutes. The mixture is then partitioned between ethyl acetate and saturated sodium chloride solution. The organic layer is dried and concentrated in vacuo. The residue thus obtained is chromatographed on silica gel, eluting with ethyl acetate. Removal of the solvent from the product fractions yielded 0.160 g of 4- (3-dimethylamino-phenylamino) -5,8-dimethoxy-quinoline-3-carbonitrile as a solid (mp: 103-105 DEG C); Mass spectrum (EI, m / e): M 348.1588.
[814] Example 243
[815] Chloro-2-fluoro-5-hydroxy-phenylamino) -5,8-dimethoxy-quinoline-3-carbonitrile
[816] A mixture of 0.223 g of 4-chloro-5,8-dimethoxy-3-quinolinecarbonitrile, 0.22 g of methyl carbonate of 4-chloro-2-fluoro-5-hydroxy- aniline and 15 mL of ethoxyethanol was refluxed Stir at temperature for 30 minutes. The mixture is cooled and then added to 100 mL of water. Sodium carbonate is added to the mixture to give a pH of 9. The product is collected, washed with water and then dried. The thus obtained solid is dissolved in a mixture of 30 mL of methyl alcohol and 20 mL of acetone. To this mixture is added 1.5 mL of 28-30% ammonium hydroxide solution. The mixture is heated at 50 &lt; 0 &gt; C for 30 minutes and then concentrated. The product was collected, washed with ethyl acetate and then dried to give 4- (4-chloro-2-fluoro-5-hydroxy-phenylamino) -5,8 Lt; / RTI &gt;dimethoxy-quinoline-3-carbonitrile; Mass spectrum (electrospray, m / e): M + H 373.9.
[817] Example 244
[818] Chloro-2-fluoro-5-hydroxy-phenylamino) -6,7,8-trimethoxy-quinoline-3-carbonitrile
[819] A mixture of 0.279 g of 4-chloro-6,7,8-trimethoxy-3-quinolinecarbonitrile, 0.22 g of methyl carbonate of 4-chloro-2-fluoro-5-hydroxy- aniline and 15 mL of ethoxyethanol Stir at reflux temperature under nitrogen for 30 minutes. The mixture is cooled and then added to 100 mL of water. Sodium carbonate is added to the mixture to give a pH of 9. The product is collected, washed with water and then dried. The thus obtained solid is dissolved in a mixture of 30 mL of methyl alcohol and 20 mL of acetone. To this mixture is added 1.5 mL of 28-30% ammonium hydroxide solution. The mixture is heated at 50 &lt; 0 &gt; C for 30 minutes and then concentrated. The product was collected, washed with ethyl acetate and then dried to give 4- (4-chloro-2-fluoro-5-hydroxy-phenylamino) -6,7- 0.0 &gt; 8-dimethoxy-quinoline-3-carbonitrile &lt; / RTI &gt; Mass spectrum (EI, m / e): M 403.0731.
[820] Example 245
[821] 4- (3-Hydroxy-2-methyl-phenylamino) -6,7-dimethoxy-quinoline-
[822] A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.123 g of 3-amino-oczole, 20 mg of pyridine hydrochloride and 10 mL of ethoxyethanol was stirred at reflux temperature for 30 minutes Lt; / RTI &gt; The mixture is cooled and then added to 40 mL of water. The mixture is adjusted to pH 7 by the addition of sodium carbonate and concentrated hydrochloric acid. The product was collected, washed with water and then dried to give 4- (3-hydroxy-2-methyl-phenylamino) -6,7-dimethoxy-quinolin- 0.174 g of carbonitrile are obtained; Mass spectrum (electrospray, m / e): M 335.9.
[823] Example 246
[824] 4- (2-Hydroxy-6-methyl-phenylamino) -6,7-dimethoxy-quinoline-
[825] A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.123 g of 2-amino-m-chlorazole, 20 mg of pyridine hydrochloride and 10 mL of ethoxyethanol was stirred at reflux temperature for 30 minutes Lt; / RTI &gt; The mixture is cooled and then added to 40 mL of water. The mixture is adjusted to pH 7 by the addition of sodium carbonate and concentrated hydrochloric acid. The product was collected, washed with water and then dried to give 4- (2-hydroxy-6-methyl-phenylamino) -6,7-dimethoxy-quinolin- 0.216 g of carbonitrile are obtained; Mass spectrum (electrospray, m / e): M 336.1363.
[826] Example 247
[827] 3- (3-Cyano-6,7-dimethoxy-quinolin-4-ylamino) -benzamide
[828] A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.136 g of 3-aminobenzamide, 20 mg of pyridine hydrochloride and 10 mL of ethoxyethanol was stirred at reflux temperature for 30 minutes under nitrogen. The mixture is cooled and then added to 40 mL of water. The mixture is adjusted to pH 7 by the addition of sodium carbonate and concentrated hydrochloric acid. The product was collected, washed with water and then dried to give 0.321 g of 3- (3-cyano-6,7-dimethoxy-quinolin-4-ylamino) -benzamide as a solid (mp: Lt; / RTI &gt; Mass spectrum (electrospray, m / e): M 349.1301.
[829] Example 248
[830] 4- (3-Bromo-4-methyl-phenylamino) -6,7-dimethoxy-quinoline-
[831] A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.186 g of 3-bromo-4-methylaniline, 20 mg of pyridine hydrochloride and 10 mL of ethoxyethanol was stirred at reflux temperature for 30 minutes Lt; / RTI &gt; The mixture is cooled and then added to 40 mL of water. The mixture is adjusted to pH 7 by the addition of sodium carbonate and concentrated hydrochloric acid. The product was collected, washed with water and then dried to give 4- (3-bromo-4-methyl-phenylamino) -6,7-dimethoxy-quinolin- 0.286 g of carbonitrile are obtained; Mass spectrum (EI, m / e): M 397.0466.
[832] Example 249
[833] 4- (3-Chloro-4-hydroxy-phenylamino) -6,7-dimethoxy-quinoline-
[834] A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.144 g of 4-amino-2-chlorophenol, 20 mg of pyridine hydrochloride and 10 mL of ethoxyethanol was stirred at reflux temperature for 30 minutes Lt; / RTI &gt; The mixture is cooled and then added to 40 mL of water. The mixture is adjusted to pH 7 by the addition of sodium carbonate and concentrated hydrochloric acid. The product was collected, washed with water and then dried to give 4- (3-chloro-4-hydroxy-phenylamino) -6,7-dimethoxy-quinolin- 0.256 g of carbonitrile are obtained; Mass spectrum (EI, m / e): M 355.0719.
[835] Example 250
[836] 6,7-Dimethoxy-4 (2-methylsulfanyl-phenylamino) -quinoline-3-carbonitrile
[837] A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.139 g of 2- (methylmercapto) aniline, 20 mg of pyridine hydrochloride and 10 mL of ethoxyethanol was stirred at reflux temperature for 30 minutes Lt; / RTI &gt; The mixture is cooled and then added to 40 mL of water. The mixture is adjusted to pH 7 by the addition of sodium carbonate and concentrated hydrochloric acid. The product was collected, washed with water and then dried to give 6,7-dimethoxy-4- (2-methylsulfanyl-phenylamino) -quinoline-3-carbonitrile 0.184 as a solid (mp: 245-247 캜) g; Mass spectrum (EI, m / e): M 351.1051.
[838] Example 251
[839] Methyl 2- (dimethylaminomethyleneamino) -4,5-diethoxybenzoate
[840] To a stirred solution of methyl 2-amino-4,5-diethoxybenzoate (4.79 g, 20 mmol) in 20 mL of DMF was added phosphorus oxychloride (2.24 mL, 24 mmol) at O <0> C over 15 min. The mixture is warmed to 55 &lt; 0 &gt; C and stirred for 45 minutes. The resulting solution is diluted with methylene chloride, cooled to 0 &lt; 0 &gt; C and then treated with 80 mL of precooled N / 1 sodium hydroxide for 5 minutes. The organic layer is separated and washed with water at 0 &lt; 0 &gt; C. The solution is dried and concentrated to give an amber oil; _{NMR (CDCl 3) δ3.00 (s} , Me 2 N).
[841] Example 252
[842] 1,4-dihydroquinoline-6,7-diethoxy-4-oxo-3-carbonitrile
[843] To a stirred solution of n-butyllithium (17.6 mL; 44 mmol in hexane 2.5 M) in 25 mL of THF was added a solution of acetonitrile (2.35 mL, 45 mmol) in 44 mL of THF at -78 <0> C for 10 min. After stirring at -78 [deg.] C for 15 min, the mixture is treated with a solution of ethyl 2- (dimethylaminomethyleneamino) -4,5-diethoxybenzoate (5.83 g, 19.8 mmol) in 30 mL of THF for 30 min. After 30 min at -78 [deg.] C, the mixture was treated with 5.7 mL (100 mmol) of acetic acid and then evaporated to dryness. The residue was slurried with water, the product precipitate was filtered off, washed with water and dried to give 4.01 g of an off-white solid; _{NMR (DMSO-d 6) d} 8.58 (s, 2-H).
[844] Example 253
[845] 4-Chloro-6,7-diethoxy-3-quinolinecarbonitrile
[846] Diethoxyquinoline-4-oxo-3-carbonitrile was treated with phosphorus oxychloride in the manner of Example 115 to give the title compound as a pink solid (mp: 170-175 占 폚) Compound.
[847] Example 254
[848] 4- [3-chloro-4- (methylthio) phenylamino] -6,7-diethoxy-3-quinolinecarbonitrile
[849] Chloro-6-ethoxy-3-quinolinecarbonitrile was reacted with 3-chloro-4- (phenylthio) aniline to give the title compound as a tan solid (mp: 88-94 ° C) The title compound is obtained.
[850] Example 255
[851] 4- [3-chloro-4- (phenylthio) phenylamino] -6,7-dimethoxy-3-quinolinecarbonitrile
[852] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile was reacted with 3-chloro-4- (phenylthio) aniline to give the title compound as a tan solid (mp: 124-130 ° C) The title compound is obtained.
[853] Example 256
[854] 4- (3-Chloro-4-fluorophenylamino) -6,7-diethoxy-3-quinolinecarbonitrile
[855] Chloro-6,7-diethoxy-3-quinolinecarbonitrile was reacted with 3-chloro-4-fluoroaniline to give the title compound as an off-white solid (mp: 194-198 ° C) &Lt; / RTI &gt;
[856] Example 257
[857] 4- (3-acetylphenylamino) -6,7-diethoxy-3-quinolinecarbonitrile
[858] Chloro-6,7-diethoxy-3-quinolinecarbonitrile was reacted with 3-aminoacetophenone to give the title compound as off-white solid (mp: 191-194 ° C).
[859] Example 258
[860] 4- (N-methylphenylamino) -6,7-diethoxy-3-quinolinecarbonitrile
[861] 4-Chloro-6,7-diethoxy-3-quinolinecarbonitrile was reacted with N-methylaniline in the manner of Example 105 to obtain the title compound as a tan solid (mp: 153-155 占 폚).
[862] Example 259
[863] 4- (phenylamino) -6,7-diethoxy-3-quinolinecarbonitrile
[864] 4-Chloro-6,7-diethoxy-3-quinolinecarbonitrile is reacted with aniline in the manner of Example 105 to obtain the title compound as a tan solid (mp: 168-170 ° C).
[865] Example 260
[866] 4- (4-fluorophenylamino) -6,7-diethoxy-3-quinolinecarbonitrile
[867] Chloro-6,7-diethoxy-3-quinolinecarbonitrile was reacted with 4-fluoroaniline in the manner of Example 105 to yield the title compound as a tan solid (mp: 177-181 [deg.] C).
[868] Example 261
[869] 4- (4-Fluoro-2-methylphenylamino) -6,7-diethoxy-3-quinolinecarbonitrile
[870] Chloro-6,7-diethoxy-3-quinolinecarbonitrile was reacted with 4-fluoro-3-methylaniline to give the title compound as a tan solid (mp: 105-108 C) &Lt; / RTI &gt;
[871] Example 262
[872] 4- (3-chlorophenylamino) -6,7-diethoxy-3-quinolinecarbonitrile
[873] Chloro-6,7-diethoxy-3-quinolinecarbonitrile was reacted with 4-fluoroaniline in the manner of Example 105 to yield the title compound as a tan solid (mp: 188-190 占 폚).
[874] Example 263
[875] 4- (3-Fluorophenylamino) -6,7-diethoxy-3-quinolinecarbonitrile
[876] Chloro-6,7-diethoxy-3-quinolinecarbonitrile was reacted with 3-fluoroaniline in the manner of Example 105 to yield the title compound as a tan solid (mp: 192-195 占 폚).
[877] Example 264
[878] 4- (3-aminophenylamino) -6,7-dimethoxy-3-quinolinecarbonitrile
[879] A solution of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile (3.73 g, 15 mmol), 1,3-diaminobenzene (4.86 g, 45 mmol), pyridine (1.21 mL, 15 mmol) The stirred mixture is refluxed for 30 minutes, cooled and then stirred with aqueous sodium bicarbonate. The resulting solid is filtered, washed with water and dried. Recrystallization from ethanol gives a brown solid (mp: 222-228 [deg.] C).
[880] Example 265
[881] 4- (3-Acetamidophenylamino) -6,7-dimethoxy-3-quinolinecarbonitrile
[882] (9.0 mmol) of acetic anhydride is added at 25 占 폚 to a solution of 4- (3-aminophenylamino) -6,7-dimethoxy-3-quinolinecarbonitrile (0.96 g, 3.0 mmol) in 9.0 mL of acetic acid . After 2 hours, the solution is evaporated to dryness and the residue is stirred with methanol. The solution is evaporated and the residue is crystallized from ethanol to give 0.50 g of an amber solid (mp: 147-150 ° C).
[883] Example 266
[884] 4- [3- (2-butynoylamino) phenylamino)] - 6,7-dimethoxy-3-quinolinecarbonitrile
[885] Isobutyl chloroformate (0.26 mL, 2.0 mmol) and N-methylmorpholine (0.22 mL, 2.0 mmol) were added to 2-butynoic acid (0.21 g, 2.5 mmol) in 8.5 mL of THF on ice. After 10 minutes, a suspension of 4- (3-aminophenylamino) -6,7-dimethoxy-3-quinolinecarbonitrile (0.32 g, 1.0 mmol) in 6.5 mL of THF was added and the resulting mixture was stirred at 25 [ Lt; / RTI &gt; and then diluted with water. The resulting solid was filtered off, washed with water, then dried and recrystallized from methanol to give 0.12 g of an off-white solid (mp: 193-196 ° C).
[886] Example 267
[887] 4- [3- (hydroxymethyl) phenylamino] -6,7-dimethoxy-3-quinolinecarbonitrile
[888] A stirred mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile (7.46 g, 30 mmol), 3-aminobenzyl alcohol (7.39 g, 60 mmol), pyridine (2.43 mL, 30 mmol) and ethoxyethanol Is refluxed for 5 hours, cooled and then stirred with aqueous sodium bicarbonate. The resulting solid is filtered, washed with water and dried. Recrystallization from methanol gives a brown solid (mp: 250-255 占 폚).
[889] Example 268
[890] 4- [3- (Chloromethyl) phenylamino] -6,7-dimethoxy-3-quinolinecarbonitrile
[891] To 14 mL of DMF was added phosphorus trichloride (0.70 mL, 8.0 mmol) at 25-30 &lt; 0 &gt; C with stirring. After 60 minutes the mixture was cooled to 0 C and a suspension of 4- [3- (hydroxymethyl) phenylamino] -6,7-dimethoxy-3-quinolinecarbonitrile (1.34 g, 4.0 mmol) in 6 mL DMF Lt; / RTI &gt; The mixture is warmed to 25 &lt; 0 &gt; C, stirred for 15 minutes, then re-cooled in an ice bath and partitioned with methylene chloride-aqueous sodium bicarbonate. The organic layer was washed with water, dried and then concentrated to give 1.15 g of an amber solid; _{NMR (CDCl 3) δ4.79 (s} , CH 2 Cl).
[892] Example 269
[893] 4- [3- (acetylthiomethyl) phenylamino] -6,7-dimethoxy-3-quinolinecarbonitrile
[894] To a stirred solution of 4- [3- (chloromethyl) phenylamino] -6,7-dimethoxy-3-quinolinecarbonitrile (0.97 g, 2.7 mmol) in 5.4 mL of DMF was added potassium thioacetate (0.93 g, 8.1 mmol) Add at 25 ° C. After 30 minutes, the mixture is partitioned with methylene chloride and water. The organic layer is washed with water, dried and concentrated. The residue was recrystallized from ethyl acetate to give 0.43 g of a yellow solid (mp: 172-177 ° C).
[895] Example 270
[896] 4- [3- (thiomethyl) phenylamino] -6,7-dimethoxy-3-quinolinecarbonitrile
[897] (1.23 g, 3.13 mmol), 12.5 mL of concentrated ammonium hydroxide, 63 mL of ethanol and 32 mL of DMF was added to a stirred mixture of 85 &lt; RTI ID = 0.0 &gt;Lt; 0 &gt; C for 2.5 hours, and then concentrated to dryness. The residue is partitioned between methylene chloride and water. The organic layer is washed with water, dried and concentrated. The residue was chromatographed on silica gel using methyl chloride-ethyl acetate-methanol to give an off-white solid; Mass spectrum (electrospray, m / e): M + H 352.1.
[898] Example 271
[899] 2- (Dimethylamino-methyleneamino) -3-methoxy-benzoic acid methyl ester
[900] 5.0 g (29.9 mmol) of 2-amino-3-methoxy-benzoic acid in 25.0 mL of DMF-DMA was heated at 100-105 &lt; 0 &gt; C for 2.5 h, then the solvent was removed to give a light purple viscous oil. After standing in the freezer, the oil solidifies to give 5.8 g (yield: 82.8%) of product as a purple-red solid; Mass spectrum (electrospray, m / e): M + H 236.9.
[901] Example 272
[902] Dihydro-8-methoxy-4-oxo-3-quinolinecarbonitrile
[903] To 35.0 mL of THF is added 26.6 mL (66.4 mmol) of n-BuLi solution at -78 &lt; 0 &gt; C for 5 minutes. To the stirred solution was added a solution of 3.55 mL (67.9 mmol) of CH ₃ CN in 65 mL of THF for 10 min, which is the time for the solution to become a white suspension, and stirring was continued for 15 min at -78 ° C. To the suspension was added a solution of 5.8 g (24.5 mmol) of 2- (dimethylamino-methyleneamino) -3-methoxy-benzoic acid methyl ester in 45 mL of THF over 30 minutes, then at -78 [deg.] C, Lt; / RTI &gt; The solution is quenched with 8.5 mL HOAc. The resulting thick slurry is stirred and then allowed to warm to room temperature. After evaporating most of the solvent, the residue is diluted with cold water. The individual solids are collected by filtration and washed with water. After drying in vacuo, 3.8 g (yield: 77.6%) of product are obtained as an off-white solid (mp: 270 캜) (decomp.); Mass spectrum (electrospray, m / e): M + H 201.1.
[904] Example 273
[905] 4-Chloro-8-methoxy-3-quinolinecarbonitrile
[906] A mixture of 3.8 g (19 mmol) of 1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarbonitrile, 40 mL of phosphorus oxychloride and 5 drops of DMF is refluxed for 0.5 hours. The mixture is evaporated to dryness and then diluted with hexane. The solid is collected, mixed with cold dilute sodium hydroxide solution and extracted with ethyl acetate several times. The organic layer is dried over sodium sulfate and filtered through a pad of silica gel. Removal of the solvent gave 3.8 g (yield: 91%) of 4-chloro-8-methoxy-3-quinolinecarbonitrile as an off-white solid. Mass spectrum (electrospray, m / e): M + H 219.1.
[907] Example 274
[908] 4 - [(3-bromophenyl) amino] -8-methoxy-3-quinolinecarbonitrile
[909] A solution of 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 309.7 mg (1.8 mmol) of 3-bromoaniline and 173.3 mg (1.5 mmol) of pyridine hydrochloride in 15 mL of 2-ethoxyethanol Is refluxed under nitrogen for 0.5 hour. After stripping the solvent, the residue is diluted with water and neutralized to pH 7-8 using dilute sodium bicarbonate solution. The precipitate was collected, washed with ether and then dried under vacuum to give 476.1 mg (89.6%) of the product as a yellow solid (mp: 210-212 ° C): Mass spectrum (electrospray, m / e) M + H &lt; / RTI &gt; 353.8, 355.8.
[910] Example 275
[911] 4- (4-Chloro-2-fluoro-phenylamino) -8-methoxy-quinoline-
[912] A similar procedure is used as described in Example 274. (1.5 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol, 173.3 mg (1.5 mmol) of pyridine hydrochloride and 240.0 mg (1.7 mmol) of the reaction mixture is heated at 100 &lt; 0 &gt; C for 2 hours. After workup, 431.3 mg (87.9%) of the product is obtained as an off-white solid (mp: 127 캜) (decomp.): Mass spectrum (electrospray, m / e): M + H 327.8, 329.9.
[913] Example 276
[914] 4- (3-Hydroxy-4-methyl-phenylamino) -8-methoxy-quinoline-
[915] A similar procedure is used as described in Example 274. (1.5 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol, 173.3 mg (1.5 mmol) of pyridine hydrochloride and 203.2 mg (1.7 mmol) of triethylamine are heated at 100 &lt; 0 &gt; C for 1.5 h. After workup, 407.7 mg (89.4%) of the product is obtained as a yellow solid (mp: 148-150 ° C): Mass spectrum (electrospray, m / e): M + H 306.9.
[916] Example 277
[917] 4- (3-Dimethylamino-phenylamino) -8-methoxy-quinoline-3-carbonitrile
[918] A similar procedure is used as described in Example 274. (1.1 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 273.3 mg (3.0 mmol) of pyridine and 261.4 mg (1.25 mmol) of 3-dimethylaminoaniline hydrochloride in 10 mL of 2-ethoxyethanol The reaction mixture is heated at 100 &lt; 0 &gt; C for 1.5 h. After workup, 294.8 mg (73.4%) of product are obtained as a dark greenish yellow solid (mp: 222-225 ° C): Mass spectrum (electrospray, m / e): M + H 319.0.
[919] Example 278
[920] 4- (4-Bromo-3-hydroxy-phenylamino) -8-methoxy-quinoline-
[921] A similar procedure is used as described in Example 274. (1.1 mmol), 4-chloro-8-methoxy-3-quinolinecarbonitrile mg (1.3 mmol) of the reaction mixture is heated at 100 &lt; 0 &gt; C for 1.5 hours. After work up, 374.1 mg (88.6%) of product are obtained as a pink solid (mp: 146 캜) (decomp.): Mass spectrum (electrospray, m / e): M + H 369.9.
[922] Example 279
[923] 4- (3-Hydroxy-4-methoxy-phenylamino) -8-methoxy-quinoline-
[924] A similar procedure is used as described in Example 274. (0.92 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol, 105.7 mg (0.92 mmol) of pyridine hydrochloride and 140.6 mg (1.0 mmol) of 2-bromobenzene are heated at 100 &lt; 0 &gt; C for 2 hours. After work up, 261.6 mg (89.0%) of the product is obtained as a pale yellow solid (mp: 138-140 ° C) (decomp.): Mass spectrum (electrospray, m / e): M + H 321.9.
[925] Example 280
[926] 8-methoxy-4- (2,4,6-trifluoro-phenylamino) -quinoline-3-carbonitrile
[927] A similar procedure is used as described in Example 274. (0.92 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol, 105.7 mg (0.92 mmol) of pyridine hydrochloride, and 2,4,6-trifluoro-aniline 148.6 mg &lt; / RTI &gt; (1.0 mmol) is heated at 100 &lt; 0 &gt; C for 2 h. After workup, 112.6 mg (37.4%) of the product is obtained as a yellow solid (mp: 297 캜) (decomp.): Mass spectrum (electrospray, m / e): M + H 330.0.
[928] Example 281
[929] 4- (3-Hydroxy-4-methyl-phenylamino) -7-methoxy-quinoline-
[930] To a suspension of 200 mg (0.91 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile and 135.5 mg (1.10 mmol) of 5-amino- o-cresol in 10 mL of 2-ethoxyethanol was added 105.6 mg 0.91 mmol). The resulting reaction mixture is refluxed for 1 hour and then the solvent is removed to give a residue. To the residue is added about 30 mL of water, and then the pH is neutralized to 7-8 by the addition of dilute sodium carbonate solution. The precipitate is collected by filtration and washed with water and ether. After drying in vacuo, 277 mg (99%) of product are obtained as a yellow solid (mp: greater than 250 캜); Mass spectrum (electrospray, m / e): M 305.9.
[931] Example 282
[932] Chloro-2-fluoro-5-hydroxy-phenylamino) -7-methoxy-quinoline-3-carbonitrile
[933] The method of Example 281 was repeated except that 218.6 mg (1.0 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile in 26 mL of 2-ethoxyethanol, 263.5 mg (1.2 mmol) of aniline and 115.6 mg ) Together. In this way, a red oil residue is obtained. And to the residue was added 10mL of methanol and NH ₄ OH (28 to 30%) 1mL. The resulting mixture is heated at 50 &lt; 0 &gt; C for 30 minutes and then the solvent is removed to give a residue. Water is added to the residue. The separated solid is collected by filtration, washed with water and ethyl / ethyl acetate (1: 1). After drying in vacuo, 142.1 mg (41.4%) of product are obtained as a brown solid (mp: 240 캜) (decomp.); Mass spectrum (electrospray, m / e): M + H 343.9, 345.8.
[934] Example 283
[935] 4- (4-Chloro-2-fluoro-phenylamino) -6-methoxy-quinoline-
[936] The procedure of Example 281 was repeated using 218.6 mg (1 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile in 10 mL of 2- ethoxyethanol, 174.7 mg (1.2 mmol) of 4- 115.6 mg (1 mmol) of pyridine hydrochloride are used together. In this way 319.8 mg of product are obtained as a yellow solid (mp:> 250 ° C); Mass spectrum (electrospray, m / e): M + H 325.9, 327.9.
[937] Example 284
[938] 4- (3-Hydroxy-4-methyl-phenylamino) -6-methoxy-quinoline-
[939] To a suspension of 218.6 mg (1.0 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and 147.8 mg (1.20 mmol) of 5-amino- o-cresol was added 115.6 mg of pyridine hydrochloride (1.0 mmol) is added. The resulting reaction mixture is refluxed for 1 hour and then the solvent is removed to give a residue. To the residue is added about 30 mL of water, and then the pH is neutralized to 7-8 by the addition of dilute sodium carbonate solution. The precipitate is collected by filtration and washed with water and ether. After drying in vacuo, 278.3 mg (91%) of product are obtained as a yellow solid (mp:> 250 ° C) (decomp.); Mass spectrum (electrospray, m / e): M + H 305.9.
[940] Example 285
[941] Chloro-2-fluoro-5-hydroxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile
[942] The method of Example 282 was performed using 218.6 mg (1.0 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile in 10 mL of 2- ethoxyethanol and 263.5 mg (1.2 mmol) of aniline (cat 800906) 115.6 mg (1.0 mmol) of hydrochloride are added. In this way, a thick oil residue is obtained. It is added 10mL methanol and NH ₄ OH (28 to 30%) 1mL in the art residue. The resulting mixture is heated at 50 &lt; 0 &gt; C for 30 minutes, the solvent is removed and the residue is triturated with water and ether in an ice bath. The separated solid is filtered off and washed with water and an ester. After drying in vacuo, 83.2 mg (24.2%) of product is obtained as a light brown solid (mp: 228-230 ° C); Mass spectrum (electrospray, m / e): M + H 343.8, 345.8.
[943] Example 286
[944] 4- (3,5-Dichloro-4-hydroxy-phenylamino) -6,7-dimethoxy-quinoline-
[945] (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol, 213.6 (1.2 mL) of 4-amino-2,6-dichlorophenol and 115.6 mg of pyridine hydrochloride the reaction mixture of (1mmol) was refluxed for 1 hour under N _2. After removal of the solvent, the residue is diluted with water and neutralized to pH 7-8 using dilute sodium bicarbonate solution. The precipitate is filtered off and washed with water and ether / ethyl acetate (1: 1). After drying in vacuo, 346.7 mg (88.8%) g of product are obtained as a yellow solid (mp: 250 DEG C): Mass spectrum (electrospray, m / e): M + H 389.8, 391.8.
[946] Example 287
[947] 4- (2-Hydroxy-4-methyl-phenylamino) -6,7-dimethoxy-quinoline-
[948] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 10 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 286. [ reacted with 147.8 mg (1.2 mmol) of 6-amino-m-cresol to yield 287.5 mg (85.8%) of product as a light brown solid (mp: 250 ° C): Mass spectrum / e): M + H 335.9.
[949] Example 288
[950] 4- (4-Hydroxy-3,5-dimethyl-phenylamino) -6,7-dimethoxy-quinoline-
[951] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 10 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 286. [ (66 mmol) of 4-amino-2,5-dimethylphenol were reacted with 164.6 mg (1.2 mmol) of 4-amino-2,5-dimethylphenol as a light brown solid (mp: 234-236 ° C) Electrospray, m / e): M + H 349.9.
[952] Example 289
[953] 4- (3-Cyano-6,7-dimethoxy-quinolin-4-ylamino) -benzamide
[954] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 10 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 286. [ (73.4%) of the product as a pale yellow solid (mp: greater than 250 캜): mass spectrum (electrospray, m / e): M @ + H 348.9.
[955] Example 290
[956] 4- (5-Chloro-2-hydroxy-phenylamino) -6,7-dimethoxy-quinoline-
[957] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 15 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 286. [ (91 mmol) of 2-amino-chlorophenol were reacted with 172.3 mg (1.2 mmol) of the title compound as a yellow solid (mp: 250 DEG C). Mass spectrum (electrospray, m / e): M + H 355.8.
[958] Example 291
[959] 4- (3,5-dibromo-4-hydroxy-phenylamino) -6,7-dimethoxy-quinoline-
[960] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 15 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 286. [ (1 mmol) were reacted with 320.3 mg (1.2 mmol) of 4-amino-2,6-dibromophenol to give 427.1 mg (89.2%) of product as a gray solid (mp: 250 ° C) (Electrospray, m / e): M + H 479.7, 481.6.
[961] Example 292
[962] 4- (4-Hydroxy-2-methyl-phenylamino) -6,7-dimethoxy-quinoline-
[963] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 15 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 286. [ mg (1 mmol) was reacted with 147.8 mg (1.2 mmol) of 4-amino-m-cresol to give 304.6 mg (90.9%) of product as a salmon solid (mp: over 250 캜): mass spectrum , &lt; / RTI &gt; m / e): M + H 335.9.
[964] Example 293
[965] 6,7-Dimethoxy-4- (pyridin-3-ylamino) -quinoline-3-carbonitrile
[966] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 15 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 286. [ (19.8%) as an orange solid (mp: 231-233 [deg.] C): mass spectrum (electrospray, m / e): M + H 306.8.
[967] Example 294
[968] 6,7-Dimethoxy-4- (3-methylsulfanyl-phenylamino) -quinoline-3-carbonitrile
[969] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 15 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 286. [ mg (1 mmol) was reacted with 167.1 mg (1.2 mmol) of 3- (methylthio) aniline to give 134.1 mg (38.2%) of product as an off-white solid (mp: 250 ° C): Mass spectrum / e): M + H = 351.9.
[970] Example 295
[971] 4- (2-Hydroxy-5-methyl-phenylamino) -6,7-dimethoxy-quinoline-
[972] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 15 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 286. [ reacted with 147.8 mg (1.2 mmol) of 2-amino-p-cresol to yield 315.0 mg (94.0%) of the product as a yellow solid (mp: 198-200 ° C): Mass Spectrum m / e): M + H 335.8.
[973] Example 296
[974] 4- (2-Chloro-4-hydroxy-phenylamino) -6,7-dimethoxy-quinoline-
[975] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 15 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 286. [ mg (1 mmol) was reacted with 270.1 mg (1.5 mmol) of 4-amino-3-chlorophenol to give 299.2 mg (84.3%) of product as a light brown solid (mp: 250 ° C): Mass spectrum m / e): M + H 335.8, 357.8.
[976] Example 297
[977] 2- (3-Cyano-6,7-dimethoxy-quinolin-4-ylamino) -benzamide
[978] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 12 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 286. [ The reaction was carried out with 177.0 mg (1.3 mmol) of the anthranylamide (mg: 1 mmol) to give 292.4 mg (84.0%) of the product as a pale yellow solid mp: 238-240.5 ° C .: mass spectrum ): M + H &lt; / RTI &gt; 348.9.
[979] Example 298
[980] 6,7-Dimethoxy-4- (4-methylsulfanyl-phenylamino) -quinoline-3-carbonitrile
[981] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 12 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 286. [ (95 mmol%) of the product as a yellow solid (mp: 235-237 ° C) was obtained by reacting 18 mg (1 mmol) of 4- (methylmercapto) aniline with 181.0 mg (1.3 mmol) Spray, m / e): M + H 351.9, 352.9, 353.8, 354.9.
[982] Example 299
[983] 4- [4- (2-hydroxy-ethyl) -phenylamino] -6,7-dimethoxy-quinoline-
[984] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 12 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 286. [ (93 mmol) of 4-aminophenethyl alcohol to yield 327.8 mg (93.9%) of a product as a white, yellow solid (mp: 208-210 ° C): Mass spectrum , &lt; / RTI &gt; m / e): M + H 349.9.
[985] Example 300
[986] 4- (2,4-dihydroxy-phenylamino) -6,7-dimethoxy-quinoline-3-carbonitrile
[987] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 12 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 286. [ (1 mmol) of 4-aminoresorcinol were reacted with 210.0 mg (1.3 mmol) of 4-aminoresorcinol to give 330.4 mg (98.0%) of product as a dark purple solid (mp: 250 ° C): Mass spectrum / e): M + H 337.9.
[988] Example 301
[989] 4- [2- (2-hydroxy-ethyl) -phenylamino] -6,7-dimethoxy-quinoline-
[990] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 12 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 286. [ mg (1 mmol) was reacted with 178.3 mg (1.3 mmol) of 2-aminophenethyl alcohol to give 218.4 mg (64.4%) of the product as a pink solid (mp: 159-162 ° C): mass spectrum e): M @ + H 349.9.
[991] Example 302
[992] 4- (3-bromophenylamino) -6,7-dihydroxy-3-quinolinecarbonitrile
[993] A stirred mixture of 4- (3-bromophenylamino) -6,7-dimethoxy-3-quinolinecarbonitrile (15.4 g, 40 mmol) and 100 g of pyridine hydrochloride was heated at 210 & , Then treated with 100 mL of concentrated ammonium hydroxide and concentrated to dryness. The residue is stirred with 1 L of water and the resulting amber solid is filtered off, washed with water and dried; Mass spectrum (electrospray, m / e): M + H 356.1, 358.1.
[994] Example 303
[995] 4- (3-bromophenylamino) -6,7-di-n-propoxy-3-quinolinecarbonitrile
[996] To a stirred mixture of 4- (3-bromophenylamino) -6,7-dihydroxy-3-quinolinecarbonitrile (1.07 g, 3.0 mmol), potassium carbonate (1.66 g, 12.0 mmol) Iodopropane (1.17 mL, 12.0 mmol) is added at 0 &lt; 0 &gt; C. The mixture is warmed to 25 &lt; 0 &gt; C, stirred for 5 hours, and then decomposed at 0 &lt; 0 &gt; C with acetate and water containing HCl to provide a pH of about 8. The organic layer is separated, washed with water, dried and concentrated. The residue is chromatographed on silica gel using methylene chloride-ethyl acetate-acetic acid to give an amorphous solid; Mass spectrum (electrospray, m / e): M + H 440.2, 442.2.
[997] Example 304
[998] 4 - [(3-bromophenyl) -N-acetylamino] -6,7-dihydroxy-3-quinolinecarbonitrile
[999] (1.78 g, 5.0 mmol), dimethylaminopyridine (60 mg, 0.50 mmol), acetic anhydride (5.0 mL) and pyridine (10 mL) were added to a solution of 4- (3-bromophenylamino) -6,7- dihydroxy- Was stirred at reflux temperature for 1.5 hours and then concentrated to dryness. The residue is stirred at 25 &lt; 0 &gt; C for 16 h with 50 mL of methanol, 5 mL of water and sodium bicarbonate (2.1 g, 25 mmol) and then concentrated to dryness. The residue is stirred with acetic acid containing water to give a pH of 4-5, the resulting solid is filtered off, washed with water and dried. The resulting solid solution in THF is passed through a silica gel pad; Concentrate the filtrate to give a tan solid; Mass spectrum (electrospray, m / e): M-H 396.3, 398.3.
[1000] Example 305
[1001] 4- (3-bromophenylamino) -6,7-di-n-butoxy-3-quinolinecarbonitrile
[1002] Dihydroxy-3-quinolinecarbonitrile (0.40 g, 1.0 mmol), 1-bromobutane (0.41 g, 3.0 mmol) was added to a solution of 4 - [(3-bromophenylamino) ), Potassium carbonate (0.30 g, 2.2 mmol) and 2.0 mL of DMF was stirred at 65-70 [deg.] C for 5 hours, concentrated to dryness and then partitioned with ethyl acetate containing ethyl acetate and water to give a pH of about 6 . The organic layer is washed with water, dried and concentrated. The residue was stirred at reflux temperature for 60 minutes with potassium carbonate (0.55 g, 4.0 mmol) and 10 mL methanol and then evaporated to dryness. The residue is partitioned between methylene chloride saturated with carbon dioxide and water (pH: about 8-9). The organic layer is separated, washed with water, dried and concentrated. The residue solution in heptane-ethyl acetate-acetic acid (60: 3: 1) is filtered through a pad of silica gel. Evaporation of the filtrate gives an amorphous solid; Mass spectrum (electrospray, m / e): M + H 467.9, 469.9.
[1003] Example 306
[1004] 4-Chloro-7-methoxy-3-quinolinecarbonitrile
[1005] In the manner of Example 115, treatment of l, 4-dihydroquinoline-7-methoxy-4-oxo-3-carbonitrile with phosphorus oxychloride afforded the title compound as a tan solid; Mass spectrum (electrospray, m / e): M + H 219.2, 221.2.
[1006] Example 307
[1007] 4- (4-Chloro-2-fluorophenylamino) -7-methoxy-3-quinolinecarbonitrile
[1008] Chloro-7-methoxy-3-quinolinecarbonitrile was reacted with 4-chloro-2-fluoroaniline in the manner of Example 274 to give the title compound as an amber solid (mp: 208-210 C) do.
[1009] Example 308
[1010] 4- (4-Chloro-2-fluorophenylamino) -7-hydroxy-3-quinolinecarbonitrile
[1011] (4-chloro-2-fluorophenylamino) -7-methoxy-3-quinolinecarbonitrile was reacted with pyridine hydrochloride at 210 占 폚 in the manner of Example 302 to give the title compound (mp: 305 &lt; 0 &gt; C).
[1012] Example 309
[1013] 4- [(4-chloro-2-fluorophenylamino) -N-acetylamino] -7-hydroxy-3-
[1014] 4- (4-chloro-2-fluorophenylamino) -7-hydroxy-3-quinolinecarbonitrile was acetacylated with acetic anhydride in the presence of dimethylaminopyridine in the manner of Example 304, De-O-acetylation with sodium bicarbonate in aqueous methanol gives the title compound as an amber solid (mp: 182-191 [deg.] C).
[1015] Example 310
[1016] 4- (4-Chloro-2-fluorophenylamino) -7-ethoxy-3-quinolinecarbonitrile
[1017] Acetylamino] -7-hydroxy-3-quinolinecarbonitrile was reacted with ethyl iodoacetate in the presence of potassium carbonate in DMF in a manner analogous to Example 305, starting from 4 - [(4-chloro-2-fluorophenylamino) Followed by de-O-acetylation with sodium bicarbonate in aqueous methanol to give the title compound as a white solid (mp: 221-224 [deg.] C).
[1018] Example 311
[1019] 4 - [(3-bromophenyl) amino] -6,7-bis (2-methoxyethoxy) -3-quinolinecarbonitrile
[1020] In a manner similar to that of Example 305, 4- (3-bromophenylamino) -6,7-dihydroxy-3-quinolinecarbonitrile was alkylated with 2-bromoethylmethyl in the presence of potassium carbonate in DMF to give The title compound is obtained as a solid (mp: 135-138 [deg.] C).
[1021] Example 312
[1022] Methyl-phenylamino) -6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinoline-3-carbonitrile
[1023] (3-morpholin-4-yl-propoxy) -quinoline-3-carbonitrile derivative, 0.12 g of 4-amino-m-cresol, 0.1 g of pyridine hydrochloride And 4 mL of 2-ethoxyethanol is stirred under nitrogen at reflux temperature for 1.5 hours. The mixture is cooled, added to a mixture of ethyl acetate and saturated sodium bicarbonate, and stirred for 15 minutes. The layers were separated and the organic layer was dried over anhydrous sodium sulfate, then filtered and the filtrate was evaporated to give a dark oil. Purification by silica gel flash chromatography with an oil gradient to methylene chloride / methanol (95: 5 to 90:10) afforded 0.23 g of the title compound as a tan solid (mp: 120-126 ° C); Mass spectrum (electrospray, m / e): M + H 449.
[1024] Example 313
[1025] 4- (3-Bromo-phenylamino) -6-methoxy-7- (3-morpholin-4- yl-propoxy) -quinoline-
[1026] The method of Example 312 was followed except that 0.3 g of 4-chloro-6-methoxy-7- (3-morpholin-4-yl-propoxy) Chloride and 4.0 mL of 2-ethoxyethanol. In this way oil was obtained and purified by silica gel flash chromatography with gradient to methylene chloride / methanol (96: 4 to 92: 8) to give 0.22 g of the title compound as an off-white solid (mp: 115-118 ° C) &Lt; / RTI &gt; Mass spectrum (ES, m / e): M + H 499.
[1027] Example 314
[1028] (3-morpholin-4-yl-propoxy) -quinoline-3-carbonitrile
[1029] The procedure of Example 312 was followed except that 0.3 g of 4-chloro-6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinoline- , 0.1 g of pyridine hydrochloride and 4.0 mL of 2-ethoxyethanol. In this way oil was obtained and purified by silica gel flash chromatography [methylene chloride / methanol (96: 4)] to yield 0.16 g of the title compound as an off-white solid (mp: 179-180 占 폚); Mass spectrum (ES, m / e): M + H 465.
[1030] Example 315
[1031] Methoxy-7- (3-morpholin-4-yl-propoxy) -quinoline-3-carbonitrile
[1032] The method of Example 312 was followed except that 0.25 g of 4-chloro-6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinoline- 0.12 mL of pyridine hydrochloride, and 4.0 mL of 2-ethoxyethanol. In this way oil was obtained and purified by silica gel flash chromatography, gradient to methylene chloride / methanol (96: 4 to 92: 8) to give 0.20 g of the title compound as a tan foam; Mass spectrum (ES, m / e): M + H 481.
[1033] Example 316
[1034] 4- (2-Aminophenylmethylamino) -6,7-diethoxy-3-quinolinecarbonitrile
[1035] In a manner similar to that of Example 61, 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile was reacted with 2-aminobenzylamine to give the title compound as off-white solid (mp: 173-177 C).
[1036] Example 317
[1037] 4- (3,4-difluorophenylmethylamino) -6,7-diethoxy-3-quinolinecarbonitrile
[1038] 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile was reacted with 3,4-difluorobenzylamine in the manner of Example 61 to obtain the title compound as a tan solid (mp: 167-169 ° C) &Lt; / RTI &gt;
[1039] Example 318
[1040] Methoxy-but-2-enoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl]
[1041] (3.17 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile and 0.6 g of diisopropylethylamine in 21 mL of tetrahydrofuran was added 4-methoxycrotonyl chloride 0.47 g (3.5 mmol) at 0 &lt; 0 &gt; C with stirring. After 1.5 h at 0 C, 0.15 g of the acid chloride is added. The mixture is diluted with 75 mL of terahydrofuran and then stirred with a mixture of brine and saturated sodium bicarbonate. 50 mL of ethyl acetate is added, the organic layer is separated and dried over magnesium sulfate. The solvent is stripped off and the residue is purified by chromatography on silica gel. Recrystallization from 1-butanol gave 1.25 g of yellow powder: Mass spectrum (electrospray, m / e): M + H 415.0, 415.9.
[1042] Example 319
[1043] 4- (4-Chloro-2-fluoro-5-hydroxy-phenylamino) -6,7-dimethoxy-quinoline-
[1044] A mixture of 0.25 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.195 g of 4-chloro-2-fluoro-5-hydroxyaniline, 0.116 g of pyridine hydrochloride and 3 mL of ethoxyethanol was purged with nitrogen At reflux temperature for 1 hour. The mixture is cooled and then added to 10 mL of water. Sodium carbonate is added to the mixture until the pH is 9. The product was collected, washed with water and then dried to give 4- (4-chloro-2-fluoro-5-hydroxy-phenylamino) -6,7- 0.327 g of dimethoxy-quinoline-3-carbonitrile are obtained; Mass spectrum (electrospray, m / e): M + H 373.9.
[1045] Example 320
[1046] 7-Benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile
[1047] To a 2.69 mL aliquot of n-butyllithium (2.5 M in hexane) in 50 mL of THF was added 3.51 mL of acetonitrile in 20 mL of THF at -78 &lt; 0 &gt; C for 10 min. After stirring at -78 [deg.] C for 30 minutes, the mixture is treated with 10 g of K17741-150 (B. Floyd) in 20 ml of THF. After 15 min at -78 [deg.] C, the stirred mixture is allowed to warm to 0 [deg.] C for a further 30 min. Then, the mixture is treated with 5 mL of acetic acid, and the mixture is heated to 25 DEG C and stirred for 30 minutes. The mixture is evaporated to dryness and then diluted with aqueous sodium bicarbonate. The resulting off-white solid is filtered off and washed with water, ethyl acetate and ether. After drying, 4.5 g of 7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile is obtained as an off-white solid (mp: greater than 255 占 폚) (decomp.); Mass spectrum (electrospray, m / e): M + H 307.
[1048] Example 321
[1049] 7-Benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile
[1050] 5 mL of oxalyl chloride (2M in methylene chloride) and 2 drops of N, N-dimethylformamide were added to a stirred suspension of 7-benzyloxy-4-hydroxy-6-methoxy-quinoline- . The mixture is refluxed for 20 minutes and slowly added aqueous sodium bicarbonate until bubbling ceases. The layers are separated, the organic layer is evaporated vigorously and then passed through a magne sol plug. Elution with 50 mL of methylene chloride followed by evaporation gives 0.6 g of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile as light yellow solid (mp: 282-284 캜); Mass spectrum (electrospray, m / e): M + H 325.
[1051] Example 322
[1052] 4- benzoyloxy-4- (4-chloro-2-fluoro-phenylamino) -6-methoxy-quinoline-
[1053] A mixture of 0.200 g of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile, 0.108 g of 4-chloro-2-fluoroaniline, 0.071 g of pyridine hydrochloride and 3 mL of ethoxyethanol And stirred at reflux temperature for 1 hour. The mixture is cooled and then added to 10 mL of water. Sodium carbonate is added to the mixture until the pH is 9. The product was collected, washed with water and then dried to give 7-benzoyloxy-4- (4-chloro-2-fluoro-phenylamino) -6-methoxy-quinoline as a solid (mp: 241- -3-carbonitrile hydrochloride &lt; / RTI &gt; Mass spectrum (electrospray, m / e): M + H 433.9.
[1054] Example 323
[1055] Chloro-2-fluoro-5-hydroxy-phenylamino) -7-methoxy-6- (3- morpholin-
[1056] 0.35 g of 4-chloro-7-methoxy-6- (3-morpholin-4-yl-propoxy) -3-quinolinecarbonitrile, 0.188 g of 4-chloro-2-fluoro- Pyridine hydrochloride and 4 mL of ethoxyethanol is stirred under nitrogen at reflux temperature for 1 hour. The mixture is cooled and then added to 10 mL of water. Sodium carbonate is added to the mixture until the pH is 9. The product was collected, washed with water and then dried to give 4- (4-chloro-2-fluoro-5-hydroxy-phenylamino) -7-methoxy- - (3-morpholin-4-yl) -propoxyl-quinoline-3-carbonitrile as an oil; Mass spectrum (electrospray, m / e): M + H 487.0.
[1057] Example 324
[1058] 4- (3-acetylphenylamino) -6,7-dimethoxy-3-quinolinecarbonitrile
[1059] In a manner similar to that of Example 274, 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile was reacted with 3-aminoacetophenone to give the title compound as a tan solid (mp: 204-26 ° C).
[1060] Example 325
[1061] 4- (3-bromophenylamino) -6,7-dimethoxymethyl-3-quinolinecarbonitrile
[1062] 4- (3-bromophenylamino) -6,7-dihydroxy-3-quinolinecarbonitrile was treated with potassium carbonate and chloromethyl ether in dimethylformamide to give a yellow solid, mp : 113-116 &lt; 0 &gt; C).
[1063] Example 326
[1064] 6-yl] -3-chloro- (E) -acrylamide &lt; / RTI &gt;
[1065] And
[1066] Example 327
[1067] 6-yl] -3-chloro- (Z) -acrylamide &lt; / RTI &gt;
[1068] (1.47 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile and 0.24 g (1.8 mmol) of diisopropylethylamine in 3 mL of tetrahydrofuran was added tetrahydrofuran (1.7 mmol) of 3-chloro-acryloyl chloride (cis / trans mixture) in 2 mL is added with stirring at 0 &lt; 0 &gt; C. After 40 minutes at 0 &lt; 0 &gt; C, the mixture is poured into a saturated sodium bicarbonate solution and the ether is extracted. The organic solution is dried over magnesium sulfate and the solvent is removed. The residue was chromatographed on silica gel to give N- [4 - [(3-bromo-phenylamino) -3-cyano-6-quinolin-6-yl] -3-chloro- (E) g: mass spectrum (electrospray, m / e): M + H 424.9, 427.0, and N- [4 - [(3-bromo- phenylamino) -3- cyano-6-quinolin- -3-chloro- (Z) acrylamide: Mass spectrum (electrospray, m / e): M + H 425.0, 427.0.
[1069] Example 328
[1070] N- [4- (3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-morpholino-
[1071] Isobutyl chloroformate (0.161g, 1.18mmol) under N ₂ in the 4-morpholin-tetrahydro-furan-2-butyric acid furnace 8mL poly (0.25g, 1.48mmol) and N- methylmorpholine (0.15g, 1.48mmol ) Add ice to ice cold solution. After stirring for 30 min, a solution of 0.25 g (0.74 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile in 6 mL of pyridine was added dropwise, Lt; / RTI &gt; The reaction is quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and then purified by thin layer chromatography eluting with 15% methanol in ethyl acetate. The product was collected and dried under vacuum to give 0.096 g (27%) of a yellow solid (mp: 145-148 ° C); Mass spectrum (electrospray, m / e): 490.1, 492.1 (M + H ^& lt ^{; +} & gt ^; ).
[1072] Example 329
[1073] N- [4- (3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-dimethylamino-
[1074] 3.8 mmol) and N-methylmorpholine (0.384 g, 3.8 mmol) in 50 mL of tetrahydrofuran under N _{2 were} added isobutyl chloroformate (0.342 g, 2.5 mmol) Add ice to ice cold solution. After stirring for 30 minutes, a solution of 0.644 g (1.9 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile in 10 mL of pyridine was added dropwise, Lt; / RTI &gt; The reaction is quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetic acid layer is concentrated and then purified by thin layer chromatography eluting with 15% methanol in ethyl acetate. The product was collected and dried under vacuum to give 0.144 g (21%) of a yellow solid (mp: 180 캜) (decomp.); Mass spectrum (electrospray, m / e): 447.9, 450.2 (M + H ^& lt ^{; +} & gt ^; ).
[1075] Example 330
[1076] N- [4- (3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-methoxy-
[1077] Isobutyl chloroformate (0.432g, 3.2mmol) under a N ₂ tetra hydro furan-4-methoxy-2-butyric acid in 20mL (0.72g, 6.32mmol) and N- methylmorpholine (0.959g, 9.78mmol) Add ice to ice cold solution. After stirring for 30 min, a solution of 0.5 g (1.58 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile in 8 mL of pyridine was added dropwise, Lt; / RTI &gt; The reaction is quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetic acid layer was concentrated and then purified by thin layer chromatography eluting with 5% methanol in chloroform. The product was collected and dried under vacuum to give 0.27 g (41%) of a yellow solid (mp: 197 <0> C) (decomp.); Mass spectrum (electrospray, m / e): 435.1, 437.0 (M + H ^& lt ^{; +} & gt ^; ).
[1078] Example 331
[1079] Amino] -3-cyano-6-quinolinyl] -4-t-butyldimethylsiloxy-2-butynamide
[1080] Isobutyl chloroformate (0.214g, 1.57mmol) when the N 4-t- butyldimethylsiloxy of under ₂ Tetra Hydro Furan 15mL -2- butyric acid (0.336g, 1.57mmol) and N- methylmorpholine (0.19g , 1.88 mmol) was added dropwise to ice cooling solution. After stirring for 30 minutes, the reaction mixture was added dropwise to a solution of 0.4 g (1.18 mmol) of 6-amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile in 3 mL of tetrahydrofuran and 1.5 mL of pyridine And then stirred at 0 ° C for 1 hour. The reaction is quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetic acid layer was concentrated and then purified by column chromatography, eluting with 60% ethyl acetate in hexanes. The product was collected and dried under vacuum to give 0.22 g (35%) of a yellow solid; Mass spectrum (electrospray, m / e): 535.1189 (M ⁺ .
[1081] Example 332
[1082] N- [4- (3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-hydroxy-
[1083] 4-tert-butyldimethylsiloxy-2-butyn-amide (60 mg, 0.122 mmol) was dissolved in acetic acid, Tetrahydrofuran and water (3: 1: 1), and then stirred at room temperature overnight. The solution is diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. Concentrate ethyl acetate to give 42.2 mg (90%) of a yellow solid; Mass spectrum (electrospray, m / e): 421.0311 (M ⁺ .
[1084] Example 333
[1085] 4- (3-hydroxymethyl-2-methylphenylamino) -6,7-dimethoxyquinoline-3-carbonitrile
[1086] (1 mmol) of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.151 g (1.1 mmol) of 3-amino- Ethoxyethanol (12 mL) is heated in an oil bath at 138-140 DEG C for 6 hours and the progress of the reaction is monitored by TLC. If TLC indicates that the starting material has disappeared, the reaction is allowed to cool and then concentrated in vacuo to a thick oil. To this oil is added 50 mL of water and then 5 mL of 1M NaHCO ₃ is added (pH ~ 8). The resulting precipitate was collected, washed with water and diethyl ether and then dried under vacuum at 65 캜 to give 0.32 g (91.5%) of the desired product as pale yellow-brown crystals (mp: 123-125 ° C) Mass spectrum (electrospray, m / e): 349.9 (M + H) &lt; ⁺ & gt ^; .
[1087] Example 334
[1088] 4- (2-amino-4,5-dimethylphenylamino) -6,7-dimethoxyquinoline-3-carbonitrile
[1089] (1 mmol) of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.410 g (3.0 mmol) of 4,5- 1 mmol) and 12 mL of 2-ethoxyethanol is heated in an oil bath at 138-140 DEG C for 1 hour and the progress of the reaction is monitored by TLC. If TLC indicates that the starting material has disappeared, the reaction is allowed to cool and then concentrated in vacuo to a thick oil. To this oil is added 50 mL of water and then 5 mL of 1M NaHCO ₃ is added (pH ~ 8). The resulting precipitate was collected, washed with water and diethyl ether and then dried under vacuum at 65 [deg.] C to give 0.587 g of the desired product (impure). The impure product is warmed to 50 mL of chloroform and 50 mL of ethyl acetate and then collected and washed with chloroform and dried to give 0.307 g (88%) of the desired pure product as yellow crystals (mp: 260-262 ° C) Spectrum (electrospray, m / e): 348.1582 (HR).
[1090] Example 335
[1091] 4- (4-ethylphenylamino) -6,7-dimethoxyquinoline-3-carbonitrile
[1092] (1mmol) of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.14mL (1.1mmol) of 4-ethylaniline, 0.116g (1mmol) of pyridine hydrochloride and 12mL of 2-ethoxyethanol The mixture is heated in an oil bath at 138-140 DEG C for 1 hour and the progress of the reaction is monitored by TLC. If TLC indicates that the starting material has disappeared, the reaction is allowed to cool and then concentrated in vacuo to a thick oil. To this oil is added 50 mL of water and then 5 mL of 1M NaHCO ₃ is added (pH ~ 8). The resulting precipitate was collected, washed with water and diethyl ether and then dried under vacuum at 65 캜 to afford 0.325 g (97.5%) of the desired product as pale cream crystals (mp: 248-250 ° C) Mass spectrum (electrospray, m / e): 333.1462.
[1093] Example 336
[1094] 4- (4-chloro-2-methylphenylamino) -6,7-dimethoxyquinoline-3-carbonitrile
[1095] (1 mmol) of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.156 g (1.1 mmol) of 4-chloro-2-methylaniline, 0.116 g (1 mmol) of pyridine hydrochloride and 2- Ethoxyethanol is heated in an oil bath at 138-140 DEG C for 24 hours and the progress of the reaction is monitored by TLC. After 24 hours, 0.156 g of 4-chloro-2-methylaniline is further added and then heated for 24 hours. If TLC indicates that the starting material has disappeared, the reaction is allowed to cool and then concentrated in vacuo to a thick oil. To this oil is added 50 mL of water and then 5 mL of 1M NaHCO ₃ is added (pH ~ 8). The sticky solid is dissolved in chloroform and passed through a moist magnesium silicate pad. The liquid is concentrated in vacuo and the residue is triturated with hexane 5 times. The resulting precipitate was collected and washed with hexane and then dried under vacuum at 65 캜 to afford 0.250 g (71%) of the desired product as brown crystals (mp: 227-229 ° C): mass spectrum , m / e): 353.8 (M + H) &lt; ⁺ & gt ^; .
[1096] Example 337
[1097] 6,7-Dimethoxy-4- (3-phenoxyphenylamino) quinoline-3-carbonitrile
[1098] (1 mmol) of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.204 g (1.1 mmol) of 3-phenoxyaniline, 0.116 g (1 mmol) of pyridine hydrochloride and 12 mL Is heated in an oil bath at 138-140 占 폚 for 3 hours and the progress of the reaction is monitored by TLC. If TLC indicates that the starting material has disappeared, the reaction is allowed to cool and then concentrated in vacuo to a thick oil. To this oil is added 50 mL of water and then 5 mL of 1M NaHCO ₃ is added (pH ~ 8). The resulting precipitate was collected and washed with water and diethyl ether and then dried under vacuum at 65 DEG C to yield 0.309 g (78%) of the desired product as a cream colored crystal (mp: 253-254 DEG C): Mass Spectrum (electrospray, m / e): 397.0 (M + H) &lt; ⁺ & gt ^; .
[1099] Example 338
[1100] 4- (4-chloro-3-trifluoromethylphenylamino) -6,7-dimethoxyquinoline-3-carbonitrile
[1101] 0.215 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.215 g of 4-chloro-3- trifluoromethylaniline, 0.116 g (1 mmol) of pyridine hydrochloride and 2- A mixture of 12 mL of ethanol is heated in an oil bath at 138-140 DEG C for 1.5 hours and the progress of the reaction is monitored by TLC. If TLC indicates that the starting material has disappeared, the reaction is allowed to cool and then concentrated in vacuo to a thick oil. To this oil is added 50 mL of water and then 5 mL of 1M NaHCO ₃ is added (pH ~ 8). The resulting precipitate was collected and washed with water and diethyl ether and then dried under vacuum at 65 캜 to afford 0.266 g (65.5%) of the desired product as a cream colored crystal (mp: 265-267 ° C): Mass Spectrum (electrospray, m / e): 408.2 (M + H) &lt; ⁺ & gt ^; .
[1102] Example 339
[1103] 4- (3-Hydroxy-phenylamino) -6, 7-dimethoxy-quinoline-3-carbonitrile
[1104] 0.7 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile and 0.38 g of 3-aminophenol are converted to 0.83 g of the title compound using the method described in Example 105: Mass spectrum Spray, m / e): 321.9, 322.8 (M + H) &lt; ⁺ & gt ^; .
[1105] Example 340
[1106] 4- (4-Methyl-phenylamino) -6, 7-dimethoxy-quinolin-3-carbonitrile
[1107] 0.7 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile and 0.317 g of 4-methylphenol were converted to 0.79 g (mp: 128-130 ° C) of the title compound using the method described in Example 105, .
[1108] Example 341
[1109] 4- (3-Hydroxy-4-methyl-phenylamino) -8-methoxy-6-nitro-quinoline-
[1110] Using 0.5 g of 4-chloro-8-methoxy-6-nitro-3-quinolinecarbonitrile and 0.28 g of 3-hydroxy-4-methylphenol, 0.3 g of the title compound was obtained Mass spectrum (electrospray, m / e): 350.9, 351.9 (M + H) &lt; ⁺ & gt ^; .
[1111] Example 342
[1112] Chloro-2-fluoro-phenylamino) -8-methoxy-6-nitro-quinoline-3-carbonitrile
[1113] Using 0.5 g of 4-chloro-8-methoxy-6-nitro-3-quinolinecarbonitrile and 0.25 mL of 4-chloro-2-fluorophenol, 0.08 g Mass spectrum (electrospray, m / e): 372.8, 374.8 (M + H) &lt; ⁺ & gt ^; .
[1114] Example 343
[1115] 4- (3-Hydroxy-4-methoxy-phenylamino) -8-methoxy-6-nitro-quinoline-
[1116] Using 0.5 g of 4-chloro-8-methoxy-6-nitro-3-quinolinecarbonitrile and 0.31 g of 3-hydroxy-4-methoxyphenol, 0.21 g Mass spectrum (electrospray, m / e): 366.9, 367.9 (M + H) &lt; ⁺ & gt ^; .
[1117] Example 344
[1118] Amino-4- (3-hydroxy-4-methyl-phenylamino) -8-methoxy-quinoline-
[1119] Using 0.2 g of 4- (3-hydroxy-4-methyl-phenylamino) -8-methoxy-6-nitro-quinoline- The title compound is converted to 0.14 g (mp: 227 <0> C) (decomp.).
[1120] Example 345
[1121] Amino-4- (3-hydroxy-4-methoxy-phenylamino) -8-methoxy-quinoline-
[1122] Using the method described in Example 196, 0.1 g of 4- (3-hydroxy-4-methoxy-phenylamino) -8-methoxy-6-nitro- quinoline- Is converted to the title compound (mp: 215 [deg.] C) (decomp.).
[1123] Example 346
[1124] N- {4- [(3-bromo-4-fluorophenyl) amino] -3-cyano-7-methoxy-6-quinolinyl} -4-bromo-2-
[1125] Using the method described in Example 172 but without reacting with dimethylamine, the title compound was obtained as white crystals from 6-amino-4- (3-bromo-4-fluoro-phenylamino) -7-methoxy-quinoline- Lt; / RTI &gt; into the title compound; Mass spectrum (electrospray, m / e): 532.8, 534.8, 536.8 (M + H) &lt; ⁺ & gt ^; .
[1126] Example 347
[1127] N- {4- [(3-bromophenyl) amino] -3-cyano-7-methoxy-6-quinolinyl} -4-chloro-2-butenamide
[1128] Using the method described in example 198, the proven byproducts of the title compound are isolated: Mass spectrum (electrospray, m / e): 471.25, 473.3 (M + H) &lt; ⁺ & gt ^; .
[1129] Example 348
[1130] N- {3-cyano-4 - [(3-iodophenyl) amino] -6- quinolinyl} -2-butynamide
[1131] 275 mg (3.27 mmol) of 2-butynoic acid are dissolved in 20 mL of THF under N _{2 and} then cooled to 0 ° C. (3.23 mmol) of isobutyl chloroformate and 355 [mu] L (3.24 mmol) of N-methylmorpholine are added, and the mixture is stirred for 10 minutes. A solution of 500 mg of 6-amino-4 - [(3-iodophenyl) amino] -3-quinolinecarbonitrile was added dropwise, the ice bath was removed after 15 minutes, and the mixture was stirred overnight at 25 ° C. The solvent is stripped, washed with water and the solid is collected. Boiling in ethyl acetate, collection and drying in vacuo afforded 228 mg of an orangeish brown solid: Mass spectrum (electrospray, m / e): M + H 453.1.
[1132] Example 349
[1133] N- {3-cyano-4 - [(3-methylphenyl) amino] -6- quinolinyl} -2-propenamide
[1134] (1.82 mmol) of 6-amino-4 - [(3-methylphenyl) amino] -3-quinolinecarbonitrile was dissolved in 1.0 mL of DMF and 6 mL of THF and then cooled to 0 ° C under N ₂ . 280 [mu] l (2.00 mmol) of triethylamine and 166 [mu] l (2.00 mmol) of acryloyl chloride are added. At 15 minutes and 1 hour, the ice bath is removed, the solvent is removed and the residue is slurried with dilute sodium carbonate. The crystals are collected and washed with water. The solid was boiled in ethyl acetate, collected and dried under vacuum to give 238 mg of a yellowish orange solid: Mass spectrum (electrospray, m / e): M + H 329.1.
[1135] Example 350
[1136] N- {4 - [(4-bromophenyl) amino] -3-cyano-6-quinolinyl}
[1137] 310 mg (1.82 mmol) of 2-butynoic acid was dissolved in 20 mL of THF and then cooled to 0 ° C under N ₂ . 480 [mu] l (3.68 mmol) of isobutyl chloroformate and 410 [mu] l (3.72 mmol) of N-methylmorpholine are added. After stirring for 20 minutes, a solution of 500 mg (1.47 mmol) of 6-amino-4 - [(4-bromophenyl) amino] -3-quinolinecarbonitrile in 1 mL of DMF and 10 mL of THF is added dropwise. After 15 minutes, the ice bath is removed and the mixture is stirred overnight at 25 ° C. After stripping the solvent, the residue is slurried with water and the solid is collected. The solid was boiled in ethyl acetate, collected and dried under vacuum to give 341 mg of a yellow solid: Mass spectrum (electrospray, m / e): M + H 405.1, 407.1.
[1138] Example 351
[1139] N- {4 - [(3-chloro-4-thiophenoxyphenyl) amino] -3-cyano-6-quinolinyl} -2-propenamide
[1140] In 2.0mL DMF and 12mL THF 6- amino-4 - [(3-chloro-4-thiophenoxy-phenyl) amino] quinoline-3-carbonitrile was dissolved 1.00g (2.48mmol), and then, N ₂ at 0 &Lt; / RTI &gt; 380 [mu] L (2.73 mmol) of triethylamine and 227 [mu] L (2.73 mmol) of acryloyl chloride are added. At 15 and 1.5 h, the ice bath is removed, the solvent is stripped off and the residue is slurried with dilute sodium bicarbonate. The solid is collected and washed with water. Recrystallization from ethyl acetate and drying in vacuo afforded 293 mg of a yellowish orange solid: Mass spectrum (electrospray, m / e): M + H 457.3, 459.3.
[1141] Example 352
[1142] N- {3-cyano-4 - [(3,4-difluorophenyl) amino] -6- quinolinyl} -2-butynamide
[1143] 42.05 mg (5.06 mmol) of 2-butynoic acid was dissolved in 40 mL of THF, and then cooled to 0 ° C under N ₂ . 556 [mu] l (5.06 mmol) of N-methylmorpholine and 658 [mu] l (5.06 mmol) of isobutyl chloroformate are added, and the mixture is stirred for 10 minutes. A solution of 1.00 g (3.37 mmol) of 6-amino-4 - [(3,4-difluorophenyl) amino] -3-quinolinecarbonitrile in 2.0 mL of hot DMF and 20 mL of THF is added dropwise. The ice bath is removed on the 15th minute, and the mixture is stirred overnight at 25 ° C. The solvent is stripped, the residue is slurried with water and the solid is collected. The solid was boiled in ethyl acetate, collected and dried in vacuo to give 735 mg of a yellow solid: Mass spectrum (electrospray, m / e): M + H 363.3.
[1144] Example 353
[1145] N- {4 - [(3-chlorophenyl) amino] -3-cyano-6-quinolinyl} -2-butynamide
[1146] 428 mg (5.09 mmol) of 2-butynoic acid are dissolved in 40 mL of THF and then cooled to 0 ° C under N ₂ . (5.09 mmol) of N-methylmorpholine and 662 μl (5.09 mmol) of isobutyl chloroformate are added, and the mixture is stirred for 10 minutes. A solution of 1.00 g (3.39 mmol) of 6-amino-4 - [(3-chlorophenyl) amino] -3-quinolinecarbonitrile in 2 mL of DMF and 20 mL of THF is added dropwise. The ice bath is removed on the 15th minute, and the mixture is stirred overnight at 25 ° C. The solvent is stripped, the residue is slurried with water and the solid is collected. It was boiled in ethyl acetate and dried under vacuum to give 975 mg of a yellow solid: Mass spectrum (electrospray, m / e): M + H 361.1, 363.2.
[1147] Example 354
[1148] N- {3-cyano-4 - [(3-isopropylphenyl) amino] -6- quinolinyl} -2-butynamide
[1149] 695 mg (8.27 mmol) of 2-butynoic acid are dissolved in 40 mL of THF and then cooled to 0 ° C under N ₂ . 1.08 mL (8.30 mmol) of isobutyl chloroformate and 910 [mu] L (8.27 mmol) of N-methylmorpholine are added, and the mixture is stirred for 10 minutes. A solution of 1.00 g (3.31 mmol) of 6-amino-4 - [(3-isopropylphenyl) amino] -3-quinolinecarbonitrile in 2.0 mL of DMF and 15 mL of THF is added dropwise. The ice bath is removed on the 15th minute, and the mixture is stirred overnight at 25 ° C. The solvent is stripped, the residue is slurried with water and the solid is collected. Recrystallization from ethyl acetate and drying under vacuum gave 329 mg of a yellowish green solid: Mass spectrum (electrospray, m / e): M + H 369.2.
[1150] Example 355
[1151] N- {3-cyano-4 - [(3-isopropylphenyl) amino] -6- quinolinyl} -2-propenamide
[1152] Hot DMF 2.0mL the 6-amino-4 - [(3-isopropylphenyl) amino] quinoline-3-carbonitrile was dissolved in acetonitrile 1.00g (3.31mmol), was added 12mL THF in the following, 0 ℃ under N ₂ And cooled. 507 [mu] L (3.64 mmol) of triethylamine and 303 [mu] L (3.64 mmol) of acryloyl chloride are added. The ice bath is removed at 15 minutes and 1 hour. The residue is slurried with dilute sodium carbonate and the solid is collected and washed with water. Recrystallization from ethyl acetate and drying in vacuo afforded 366 mg of an orange solid: Mass spectrum (electrospray, m / e): M + H 357.1.
[1153] Example 356
[1154] 6-Amino-4 - [(3-isopropylphenyl) amino] -3-quinolinecarbonitrile
[1155] Of 10% Pd / C 0.5g was added under N ₂ in a round bottom flask was filled with, and then 250mL ethanol. 4.818 g (14.5 mmol) of 4 - [(3-isopropylphenyl) amino] -6-nitro-3-quinolinecarbonitrile and 1.14 mL (36.2 mmol) of hydrazine anhydride were added and heated to reflux. At 1.5 h, the hot mixture was filtered through celite, stripping the solvent and drying in vacuo to give 4.30 g of a yellow solid: Mass spectrum (electrospray, m / e): M + H 303.1.
[1156] Example 357
[1157] 4 - [(3-isopropylphenyl) amino] -6-nitro-3-quinolinecarbonitrile
[1158] A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 mL of ethanol and 3.48 g (25.8 mmol) of 3-isopropylaniline is heated to reflux under N ₂ . Heat is removed at 4 hours and made basic with saturated sodium bicarbonate. The solvent is stripped and then azeotropically mixed with ethanol. The residue is slurried with hexane and the solid is collected. The residue was dissolved in ethyl acetate and stirred with Darco followed by filtration through celite, stripping the solvent and drying in vacuo to give 5.289 g of a yellow solid: mass spectrum (electrospray, m / e): M + H = 333.1.
[1159] Example 358
[1160] 4- (3-Bromo-phenylamino) -6- (3-pyrrolidin- 1 -yl- propylamino) -quinoline- 3-carbonitrile
[1161] 0.64 g (3.69 mmol) of 3- (pyrrolidin-1-yl) propionaldehyde dimethyl acetal is dissolved in 10 mL of water and then oxidized to pH 1 using concentrated HCl. Heat to 40 &lt; 0 &gt; C for 90 minutes, remove heat, and neutralize with sodium bicarbonate. 500 mg (1.47 mmol) of 6-amino-4- (3-bromo-phenylamino) -quinoline-3-carbonitrile is dissolved in 100 mL of ethanol and then acetic acid is added until the pH is 3-4. The deprotected aldehyde is added to the amine solution and then stirred at 25 &lt; 0 &gt; C for 0.5 hour. 94 mg (1.47 mmol) of sodium cyanoborohydride are slowly added and the mixture is stirred overnight. The solvent is stripped off and then partitioned between chloroform and water. The organic layer is washed with brine and dried over sodium sulfate. The solvent is stripped and then filtered through a pad of silica gel using 10% methanol / chloroform followed by 20% methanol / chloroform / 1% ammonium hydroxide. The solvent was stripped and dried in vacuo to give 143 mg of a tan solid: Mass spectrum (electrospray, m / e): M + H 450, 452.1.
[1162] Example 359
[1163] 4- (3-azido-phenylamino) -6,7-dimethoxy-quinolin-3-carbonitrile
[1164] (2.00 mmol) of 4- (3-amino-phenylamino) -6,7-dimethoxy-quinoline-3-carbonitrile is dissolved in 25 mL of 80% acetic acid in water. After cooling to 0 &lt; 0 &gt; C, 152 mg (2.21 mmol) of sodium nitrate in 2.2 mL of water are added. After 10 minutes, 144 mg (2.21 mmol) of sodium azide in 2.2 mL of water are added. The solvent is stripped at 1.5 hours and the residue is dissolved in hot ethyl acetate. Washed with saturated sodium bicarbonate, water and brine, and dried over sodium sulfate. The solvent is stripped off, redissolved in 60% ethyl acetate / methylene chloride and filtered through a pad of silica gel. The solvent was stripped and dried under vacuum to give 526 mg of a brown solid: Mass spectrum (electrospray, m / e): M + H 347.1.
[1165] Example 360
[1166] 6-Amino-4 - [(4-chloro-2-fluorophenyl) amino] -7-methoxy-3-quinolinecarbonitrile
[1167] (1.34 mmol) of 4 - [(4-chloro-2-fluorophenyl) amino] -7-methoxy-6-nitro-3-quinolinecarbonitrile, 20 mL of ethanol and 1.52 mL (6.71 mmol) the mixture is heated to reflux under N _2. Heat is removed at 3 hours, ice water is added, and then basified with saturated sodium bicarbonate. After stirring for several hours, it is extracted with chloroform. The organic layer was dried with sodium sulfate, stripped of solvent and dried under vacuum to give 350 mg of a green solid: Mass spectrum (electrospray, m / e): M + H = 342.9, 344.8.
[1168] Example 361
[1169] 4 - [(4-chloro-2-fluorophenyl) amino] -7-methoxy-6-nitro-3-quinolinecarbonitrile
[1170] 4-Chloro-7-methoxy-6-nitro-quinoline-3-carbonitrile 5.107g (19.0mmol), ethanol 20mL and 4-chloro-heating a mixture of 2-fluoro-aniline 2.55mL (22.8mmol) under N ₂ And refluxed. Heat is removed at 3.5 hours, ice water is added, and then basified with saturated sodium bicarbonate. The solvent is stripped and then azeotropically mixed with ethanol. The residue is slurried with hexane, the solid is collected and washed with water. Mass spectrum (electrospray, m / e): M + H = &lt; / RTI &gt;&lt; RTI ID = 0.0 &gt; 372.8, 374.8.
[1171] Example 362
[1172] 4 - [(3,4-dichlorophenyl) amino] -6-nitro-3-quinolinecarbonitrile
[1173] A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile, 250 mL of ethanol and 4.17 g (25.6 mmol) of 3,4-dichloroaniline is heated to reflux under N ₂ . Heat is removed at 3.5 hours and then made basic with saturated sodium bicarbonate. The solvent is stripped and then azeotropically mixed with ethanol. The residue is slurried with hexane, the solid is collected and washed with water. (Electrospray, m / e): M + H = &lt; RTI ID = 0.0 &gt; 359.1, 361.0.
[1174] Example 363
[1175] 6-Amino-4 - [(3-methylsulfanylphenyl) amino] -3-quinolinecarbonitrile
[1176] A mixture of 4.55 g (13.5 mmol) of 4 - [(3-methylsulfanylphenyl) amino] -6-nitro-3-quinolinecarbonitrile, 250 mL of ethanol, 0.46 g of 10% Pd / C and 1.06 mL (33.8 mmol) The mixture is heated to reflux. At the fourth hour 0.5 equivalent of hydrazine is added and at 5 hours the hot mixture is filtered through celite. The solvent was stripped and dried in vacuo to give 4.068 g of a brown solid: Mass spectrum (electrospray, m / e): M + H 307.1.
[1177] Example 364
[1178] 4 - [(3-methylsulfanylphenyl) amino] -6-nitro-3-quinolinecarbonitrile
[1179] A mixture of 4-chloro-6-nitro-3-quinoline hydrochloride 5.00g (21.5mmol), ethanol and 200mL 3-methylsulfanyl-aniline 3.18mL (25.8mmol) then heated to reflux under N _2. Heat is removed at 2 hours and then basified using saturated sodium bicarbonate. The solvent is stripped and then dried in air. The residue is washed with hexane, the solid is collected and washed with water. After dissolving in ethylacetate and stirring with Darco, the solvent was stripped and dried under vacuum to give 4.848 g of a yellow solid: Mass spectrum (electrospray, m / e): M + H = 337.1.
[1180] Example 365
[1181] 4 - [(3-Trifluoromethoxyphenyl) amino] -6-nitro-3-quinolinecarbonitrile
[1182] A mixture of 4-chloro-6-nitro-3-quinoline hydrochloride 5.00g (21.5mmol), ethanol and 200mL 3-trifluoromethoxy aniline 3.4mL (25.3mmol) then heated to reflux under N _2. Heat is removed at 5 h and then made basic with saturated sodium bicarbonate. The solvent is stripped, the residue is slurried with hexane, then collected and washed with water. (Electrospray, m / e): &lt; RTI ID = 0.0 &gt; m / e &lt; / RTI &gt;: M &lt; RTI ID = 0.0 &gt; + H = 374.8.
[1183] Example 366
[1184] 4- (3-Dimethylamino-phenylamino) -6,7-dimethoxy-quinoline-3-carbonitrile
[1185] 1.25 g (5 mmol) of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile in 10 mL of 2-methoxyethanol and 1.05 g (5 mmol) of N, N-dimethyl- Is refluxed in an oil bath at 154 占 폚 for 2 hours. Cool the recrystallized solid from water to give 0.4 g (19%) of 4- (3-dimethylamino-phenylamino) -6,7-dimethoxy-quinolin-3-carbonitrile which is soluble at 246-249 ° C &Lt; / RTI &gt; Mass spectrum (electrospray, m / e): 349.2, (M + 2H) ⁺² 174.9.
[1186] Example 367
[1187] 6,7-Dimethoxy-4- (4-methoxy-2-methyl-phenylamino) -quinoline-
[1188] (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol, 164.6 mg (1.2 mmol) of 4-methoxy-2-methyl- aniline and 11.56 the reaction mixtures mg (1mmol) under N ₂ was refluxed for 3 hours. After removal of the solvent, the residue is diluted with water and the pH is neutralized to 7-8 using dilute sodium bicarbonate solution. The precipitate is filtered off and washed with water and ether. After drying in vacuo, 250.2 mg (71.7%) of product are obtained as a reddish solid (mp: 131 DEG C) (decomp.): Mass spectrum (electrospray, m / e): M + H = 349.9.
[1189] Example 368
[1190] 3- (3-Cyano-6,7-dimethoxy-quinolin-4-ylamino) -2-methyl-
[1191] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 12 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 367. [ mg (1 mmol) was reacted with 196.5 mg (1.3 mmol) of 3-amino-2-methylbenzoic acid to give 89.6 mg (24.7%) of product as a gray solid mp: 242-245 ° C .: mass spectrum , &lt; / RTI &gt; m / e): M + H 364.0.
[1192] Example 369
[1193] 4- (3-Hydroxy-4-methoxy-phenylamino) -6,7-dimethoxy-quinoline-
[1194] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 10 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 367. [ (89 mmol%) of the product as a gray solid (mp: 254-256 ° C) was obtained by reacting 167.0 mg (1.2 mmol) of 5-amino-2-methoxyphenol Spray, m / e): M + H 351.2.
[1195] Example 370
[1196] 4- (3-Chloro-4-methyl-phenylamino) -6,7-dimethoxy-quinoline-
[1197] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 10 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 367. [ 350 mg (99.4%) of the product is obtained as a yellow solid (mp: greater than 250 캜) by reaction with 170.0 mg (1.2 mmol) of 2-chloro-4-amino- , &lt; / RTI &gt; m / e): M + H 353.9, 355.8.
[1198] Example 371
[1199] 6,7-Dimethoxy-4- (4-phenoxy-phenylamino) -quinoline-3-carbonitrile
[1200] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 12 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 367. [ 28.3 mg (71.3%) of the product was obtained as a light yellow solid (mp: 239-241 占 폚) by reaction with 222.3 mg (1.2 mmol) of 4-phenoxyaniline. e): M @ + H 397.9.
[1201] Example 372
[1202] 4- (5-Chloro-2-methoxy-phenylamino) -6,7-dimethoxy-quinoline-
[1203] Chloro-6,7-dimethoxy-3-quinolinecarbonitrile 248.7 (1 mmol) in the presence of 12 mL of 2-ethoxyethanol and 115.6 mg (1 mmol) of pyridine hydrochloride using a similar procedure as described in example 367. [ (65 mmol%) of the product as a cream colored solid (mp: 200 to 202 ° C) was obtained by reacting 18 mg (1 mmol) of 5-chloro-o-anisidine with 189.1 mg (1.2 mmol) , &lt; / RTI &gt; m / e): M + H 369.9, 371.8.
[1204] Example 373
[1205] 4- (4-Chloro-2-fluoro-phenylamino) -6,7-dihydroxy-quinoline-
[1206] A mixture of 0.358 g of 4- (4-chloro-2-fluoro-phenylamino) -6,7-dimethoxy-quinoline-3-carbonitrile and 3 g of pyridine hydrochloride was stirred at 210-220 &Lt; / RTI &gt; The mixture is cooled and then added to 50 mL of 3% ammonium hydroxide solution. The product was collected, washed with water and then dried to give 4- (4-chloro-2-fluoro-phenylamino) -6,7-dihydroxy-quinolin-3 as a solid (mp: 270-272 ° C) (EI, m / e): &lt; RTI ID = 0.0 &gt; M 329.0363. &Lt; / RTI &gt;
[1207] Example 374
[1208] 4- (3-Hydroxy-2-methyl-phenylamino) -6,7-dimethoxy-quinoline-
[1209] A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.123 g of 3-amino-o-cresol, 20 mg of pyridine hydrochloride and 10 mL of ethoxyethanol was stirred at reflux temperature for 30 minutes . The mixture is cooled and then added to 40 mL of water. Sodium carbonate and concentrated hydrochloric acid are added to the mixture and the pH is adjusted to 7. The product was collected, washed with water and then dried to give 4- (3-hydroxy-2-methyl-phenylamino) -6,7-dimethoxy-quinolin- 0.174 g of carbonitrile are obtained: Mass spectrum (electrospray, m / e): M + H 335.9.
[1210] Example 375
[1211] 4- (3-Chloro-4-methoxy-phenylamino) -6,7-dimethoxy-quinoline-
[1212] A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.158 g of 3-chloro-p-anisidine, 20 mg of pyridine hydrochloride and 10 mL of ethoxyethanol was stirred at reflux temperature for 30 minutes Lt; / RTI &gt; The mixture is cooled and then added to 40 mL of water. Sodium carbonate and concentrated hydrochloric acid are added to the mixture and the pH is adjusted to 7. The product was collected, washed with water and then dried to give 4- (3-chloro-4-methoxy-phenylamino) -6,7-dimethoxy-quinolin- 0.324 g of carbonitrile are obtained: Mass spectrum (electrospray, m / e): M 369.0860.
[1213] Example 376
[1214] 6,7-Dimethoxy-4- (4-trifluoromethyl-phenylamino) -quinoline-3-carbonitrile
[1215] A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.322 g of 4- (trifluoromethyl) aniline, 20 mg of pyridine hydrochloride and 10 mL of ethoxyethanol was stirred at reflux temperature for 30 minutes Lt; / RTI &gt; The mixture is cooled and then added to 40 mL of water. Sodium carbonate and concentrated hydrochloric acid are added to the mixture and the pH is adjusted to 7. The product was collected, washed with water and then dried to give 6,7-methoxy-4- (4-trifluoromethyl-phenylamino) -quinoline-3-carbonitrile as a solid (mp: 0.268 g was obtained: Mass spectrum (EI, m / e): M 373.1031.
[1216] Example 377
[1217] 4- (3,4-dibromophenylamino) -6-nitroquinoline-3-carbonitrile
[1218] A mixture of 6.20 g (26.6 mmol) of 4-chloro-6-nitroquinoline-3-carbonitrile and 8.00 g (31.9 mmol) of 3,4-dibromoaniline in 160 mL of EtOH is refluxed under N ₂ for 5 hours. The addition of saturated NaHCO _3, followed by removal of the volatiles. The residue was slurried with hexane, collected, washed with hexane and H ₂ O, and dried. The insoluble material is repeatedly extracted with boiling EtOAc, then the solution is filtered through silica gel. Removal of the solvent gave 3.80 g of 4- (3,4-dibromophenylamino) -6-nitroquinoline-3-cannonitrile as a green solid: Mass spectrum (electrospray, m / e): M + H 448.9.
[1219] Example 378
[1220] 6-Amino-4- (3-trifluoromethylphenylamino) quinoline-3-carbonitrile
[1221] A mixture of 6.0 g (16.8 mmol) of 6-nitro-4- (3-trifluoromethylphenylamino) quinoline-3-carbonitrile and 18.9 g (83.8 mmol) SnCl ₂ .2H ₂ O in 240 mL of EtOH was treated under N ₂ Reflux for 1 hour. Add ice water, then add NaHCO ₃ to pH 8. The mixture was stirred for 2 hours, followed by the addition of CHCl _3. It was added Darko, filtered through anhydrous MgSO _4, and then the extracts were then evaporated. The residue was purified using 10% MeOH in CHCl ₃ and filtered through silica gel. The solvent was evaporated and dried under vacuum (40 캜) to give 4.87 g of 6-amino-4- (3-trifluoromethylphenylamino) quinolin-3-carbonitrile as a brown solid: Mass spectrum (electrospray, m / e): M + H 329.1.
[1222] Example 379
[1223] 6-Amino-4- (3,4-dibromophenylamino) quinoline-3-carbonitrile
[1224] In the same manner as in Example 378, 4.90 g of 4- (3,4-dibromophenylamino) -6-nitroquinoline-3-carbonitrile and 12.4 g of SnCl ₂ .2H ₂ O were prepared. 1.25 g of 6-amino-4- (3,4-dibromophenylamino) quinoline-3-carbonitrile as brown solid: mass spectrum (electrospray, m / e): M + H 416.9, 418.9.
[1225] Example 380
[1226] N- [3-cyano-4- (3,4-dibromophenylamino) quinolin-6-yl]
[1227] To a solution of 0.217 g (2.15 mmol) of Et ₃ N and ₂ -amino-4- (3,4-dibromophenylamino) quinoline-3-carbonitrile (0.750 g, 1.79 mmol) in 10 mL of THF at 0 & And treated with 0.195 g (2.15 mmol) acryloyl chloride. After stirring at 25 &lt; 0 &gt; C overnight, the solvent is evaporated and the residue is slurried with water and then collected. The residue was boiled twice with EtOAc and dried under vacuum (50 DEG C) to give N- [3-cyano-4- (3,4-dibromophenylamino) quinolin- Amide: Mass spectrum (electrospray, m / e): 470.9, 472.9.
[1228] Example 381
[1229] N- [4- (3-bromophenylamino) -3-cyanoquinolin-6-yl] propionamide
[1230] In the same manner as in Example 380, 1.00 g of 6-amino-4- (3-bromophenylamino) quinoline-3-carbonitrile, 0.359 g of Et ₃ N and 0.328 g of propionyl chloride were prepared. Mass spectrometry (electrospray, m / e): M + H 395.1 &lt; RTI ID = 0.0 &gt; , 397.0.
[1231] Example 382
[1232] (E) -but-2-enoic acid [4- (3-bromophenylamino) -3-cyanoquinolin-
[1233] A solution of 0.637 g (7.40 mmol) of (E) -but-2-enoic acid in 25 mL of THF is cooled on ice under N ₂ . Isobutyl chloroformate (1.01 g, 7.40 mmol) and N-methylmorpholine (0.747 g, 7.40 mmol) were added and the solution was then cooled and stirred for 10 min. A slurry of 1.00 g (2.96 mmol) of 6-amino-4- (3-bromophenylamino) quinoline-3-carbonitrile in 15 mL of THF is added and the mixture is stirred overnight at 25 <0> C. The mixture is evaporated, the residue is slurried with water, then collected and dried. The residue was boiled twice with EtOAc and dried in vacuo (50 DEG C) to give (E) -but-2-enoic acid [4- (3- bromophenylamino) -3- cyanoquinoline- 6-yl] amide as a white solid: mass spectrum (electrospray, m / e): M + H 406.9, 408.9.
[1234] Example 383
[1235] N- [4- (3-bromophenylamino) -3-cyanoquinolin-6-yl] -2-methylacrylamide
[1236] In the same manner as in Example 380, 0.500 g of 6-amino-4- (3-bromophenylamino) quinoline-3-carbonitrile, 0.194 g of Et ₃ N and 0.202 g of methacryloyl chloride were prepared. 0.317 g of N- [4- (3-bromophenylamino) -3-cyanoquinolin-6-yl] -2-methylacrylamide as a yellow solid: mass spectrum (electrospray, m / e) M + H 406.8, 408.8.
[1237] Example 384
[1238] 4- (3-Fluorophenylamino) -6-nitroquinoline-3-carbonitrile
[1239] In the same manner as in Example 377, 5-chloro-6-nitroquinoline-3-carbonitrile and 2.86 g of 3-fluoroaniline were prepared. The crude product is dissolved in alternate EtOAc, treated with Darco, and filtered through celite. The solvent was stripped and then dried under vacuum (50 DEG C) to give 5.77 g of 4- (3-fluorophenylamino) -6-nitroquinolin-3-carbonitrile as a yellowish orange solid: mass spectrum Electrospray, m / e): M + H 309.2.
[1240] Example 385
[1241] 6-Amino-4- (3-fluorophenylamino) quinoline-3-carbonitrile
[1242] In the same manner as in Example 378, 5.04 g of 4- (3-fluorophenylamino) -6-nitroquinoline-6-carbonitrile and 18.5 g of SnCl ₂ .2H ₂ O were prepared. It is not necessary to filter through silica. Mass spectrometry (electrospray, m / e): M + H 279.1. &Lt; RTI ID = 0.0 &gt; 1 &lt; / RTI &gt;
[1243] Example 386
[1244] 4- (3-dimethylaminophenylamino) -6-nitroquinoline-3-carbonitrile
[1245] In the same manner as in Example 377, 5.00 g of 4-chloro-6-nitroquinoline-3-carbonitrile, 5.38 g of 3-dimethylaminoaniline dihydrochloride and 5.17 g of triethylamine were prepared. The crude product is dissolved in EtOAc, treated with Darco, filtered through celite, evaporated and dried under vacuum (50 &lt; 0 &gt; C). 5.62 g of 4- (3-dimethylaminophenylamino) -6-nitroquinoline-3-carbonitrile as reddish brown crystals: mass spectrum (electrospray, m / e): M + H 334.2.
[1246] Example 387
[1247] 4- (4-dimethylaminophenylamino) -6-nitroquinoline-3-carbonitrile
[1248] In the same manner as in Example 386, from 5.00 g of 4-chloro-6-nitroquinoline-3-carbonitrile, 5.38 g of 4-dimethylaminoaniline dihydrochloride and 5.17 g of triethylamine. 5.58 g of 4- (4-dimethylaminophenylamino) -6-nitroquinoline-3-carbonitrile as reddish-brown crystals were obtained: Mass spectrum (electrospray, m / e): M + H334.2.
[1249] Example 388
[1250] 6-Amino-4- (3-dimethylaminophenylamino) quinoline-3-carbonitrile
[1251] A mixture of 5.00 g (15.0 mmol) of 4- (3-dimethylaminophenylamino) -6-nitro-quinoline-3-carbonitrile, 1.20 g (37.5 mmol) hydrazine anhydride and 0.5 g 10% Pd / And refluxed under N ₂ for 1.3 hours. The reaction is filtered through celite, the celide is washed with EtOH, and the filtrate and washings are combined. The solvent was evaporated and dried under vacuum (50 캜) to give 6-amino-4- (3-dimethylaminophenylamino) quinolin-3-carbonitrile as a reddish brown solid: mass spectrum (electrospray, m / e ): M &lt; + &gt; H 303.9.
[1252] Example 389
[1253] 6-Amino-4- (4-dimethylaminophenylamino) quinoline-3-carbonitrile
[1254] Prepared from 4- (4-dimethylaminophenylamino) -6-nitroquinoline-3-carbonitrile (5.00 g), 1.20 g of hydrazine anhydride and 0.500 g of 10% Pd / C in the same manner as in Example 388. After first washing with MeOH (discard), the product is extracted with DMF. The final solvent is collected separately, evaporated and the residue is dried under vacuum (50 &lt; 0 &gt; C). Mass spectrum (electrospray, m / e): M + H 303.9.
[1255] Example 390
[1256] But-2-ynoic acid [4- (3-fluorophenylamino) -3-cyanoquinolin-6-yl]
[1257] In the same manner as in Example 382, 0.756 g of but-2-ynoic acid, 1.23 g of isobutyl chloroformate, 0.908 g of N-methylmorpholine and 0.908 g of 6-amino-4- (3-fluorophenylamino) - canonitrile. &Lt; / RTI &gt; 1.07 g of but-2-ynoic acid [4- (3-fluorophenylamino) -3-cyanoquinolin-6-yl] amide as a yellow solid: mass spectrum (electrospray, m / e): 345.1 .
[1258] Example 391
[1259] N- [3-cyano-4- (3-dimethylaminophenylamino) quinolin-6-yl]
[1260] In the same manner as in Example 88, 1.00 g of 6-amino-4- (3-dimethylaminophenylamino) quinoline-3-carbonitrile, 0.400 g of triethylamino and 0.360 g of acryloyl chloride were prepared. 0.880 g of N- [3-cyano-4- (3-dimethylaminophenylamino) quinolin-6-yl] acrylamide as an orange solid: mass spectrum (electrospray, m / e): 358.1.
[1261] Example 392
[1262] N- [3-cyano-4- (4-dimethylaminophenylamino) quinolin-6-yl]
[1263] In the same manner as in Example 380, 1.00 g of 6-amino-4- (4-dimethylaminophenylamino) quinoline-3-carbonitrile, 0.400 g of triethylamine and 0.360 g of acryloyl chloride were prepared. (Electrospray, m / e): 358.2 &lt; RTI ID = 0.0 &gt; (m / e) &lt; / RTI &gt; as a brownish orange solid: .
[1264] Example 393
[1265] But-2-ynoic acid [3-cyano-4- (3-dimethylaminophenylamino) quinolin-
[1266] In the same manner as in Example 382, 0.694 g of but-2-ynoic acid, 1.13 g of isobutyl chloroformate, 0.833 g of N-methylmorpholine and 0.833 g of 6-amino-4- (3-dimethylaminophenylamino) - canonitrile. &Lt; / RTI &gt; (Electrospray, m / e): &lt; RTI ID = 0.0 &gt; m / e &lt; / RTI &gt;: M &lt; RTI ID = 0.0 &gt; + H 370.2.
[1267] Example 394
[1268] But-2-ynoic acid [3-cyano-4- (4-dimethylaminophenylamino) quinolin-
[1269] In the same manner as in Example 382, 0.694 g of but-2-ynoic acid, 1.13 g of isobutyl chloroformate, 0.833 g of N-methylmorpholine and 0.33 g of 4- (4-dimethylaminophenylamino) quinolin- g. 1.13 g of but-2-ynoic acid [3-cyano-4- (4-dimethylaminophenylamino) quinolin-6-yl] amide as a red-brick solid: mass spectrum (electrospray, m / e) M + H 370.2.
[1270] Example 395
[1271] 4- (3-bromophenylamino) -6-dimethylaminoquinoline-3-carbonitrile hydrochloride
[1272] In the same manner as in Example 377, 4-chloro-6-dimethylaminoquinoline-3-carbonitrile was prepared from 0.400 g and 3-bromoaniline. The crude product is boiled twice with EtOAc and dried under vacuum (50 &lt; 0 &gt; C). 0.621 g of 4- (3-bromophenylamino) -6-dimethylaminoquinoline-3-carbonitrile as a brown powder: mass spectrum (electrospray, m / e): M + H 366, 368.9.
[1273] Example 396
[1274] 6-Dimethylamino-4- (3-methoxyphenylamino) quinoline-3-carbonitrile hydrochloride
[1275] In the same manner as in Example 395, 0.400 g of 4-chloro-6-dimethylaminoquinoline-3-carbonitrile and 0.256 g of 3-methoxyaniline were prepared. 0.532 g of 6-dimethylamino-4- (3-methoxyphenylamino) quinoline-3-carbonitrile as a brown powder: mass spectrum (electrospray, m / e): M + H 318.9.
[1276] Example 397
[1277] 2-Bromo-N- [4- (3-bromophenylamino) -3-cyanoquinolin-6-yl] acetamide
[1278] In the same manner as in Example 380, from 1.50 g of 6-amino-4- (3-bromophenylamino) quinoline-3-carbonitrile, 0.538 g of triethylamine and 1.08 g of bromoacetyl bromide. 1.55 g of 2-bromo-N- [4- (3-bromophenylamino) -3-cyanoquinolin-6-yl] acetamide as a tan solid: mass spectrum (electrospray, m / e) : M @ + H 458.9, 460.9.
[1279] Example 398
[1280] 6-Iodo-4- (3-methoxyphenylamino) quinoline-3-carbonitrile
[1281] In the same manner as in Example 377, 1.00 g of 4-chloro-6-iodoquinoline-3-carbonitrile and 0.469 g of 3-methoxyaniline were prepared. The crude product is filtered through silica gel using 20% EtOAc in CH ₂ Cl ₂ , evaporated and dried under vacuum (50 ° C). 1.09 g of 6-iodo-4- (3-methoxyphenylamino) quinoline-3-carbonitrile as yellow crystals: mass spectrum (electrospray, m / e): M + H 401.9.
[1282] Example 399
[1283] Chloro-4-fluoro-phenylamino) -3-cyano-7-ethoxy-quinolin-6-yl] -amide
[1284] 5-Methoxy-2-methyl-4-nitroacetanilide
[1285] 182.1 g (1.0 mmol) of 5-methoxy-2-methyl-4-nitroaniline in 400 mL of acetic acid was heated and refluxed. To the hot solution is added 320 mL of acetic anhydride. The mixture is refluxed for 1/2 hour and then poured into ice. The solid is collected, washed twice with water and twice with concentrated NH ₄ OH (this step converts diacetate to mono-acetate). The solids are then dried in air. The solid is dissolved in 1400 mL of boiling chloroform, treated with MgSO ₄ and Norit, and then filtered while hot. The filtrate is boiled and then 500 mL of hexane is added. The mixture is cooled in an ice bath. The solid was collected and 145.9 g (65%) of product was collected as an orange solid.
[1286] 5-ethoxy-2-methyl-4-nitroacetanilide
[1287] A mixture of 186 g (830 mmol) of 5-methoxy-2-methyl-4-nitroaniline and 105.5 g (2.49 mol) of LiCl in 1115 mL of DMF was mechanically stirred under reflux for 12 hours without using a condenser. The dark orange solution is cooled to room temperature and left to stand overnight. To the solution is added 114.65 g (830 mmol) of powdered K ₂ CO _{3 and} 265.4 mL (3.32 mol) of ethyl iodide. The mixture is slowly heated with stirring. At about 70 [deg.] C, gas (preferably ethyl chloride) is released rapidly. After releasing most of the gas, it is continuously heated to the reflux temperature. The mixture is refluxed for 5 hours and then poured into ice water. The solid is collected, washed several times with water, and then dried in air. It was dissolved in chloroform 2L boiling the solids, treated with MgSO _4, and then filtered while hot. The filtrate is boiled and then diluted with 1.5 L of hexane. The mixture was cooled and the solid was collected, yielding 105 g (53%) of a yellow solid.
[1288] 2-Acetylamino-4-ethoxy-5-nitro-benzoic acid
[1289] A solution of 217.3 g of potassium permanganate and 75.23 g of magnesium sulfate in 5000 mL of water is heated to 80 占 폚. Then, 119 g (0.5 mol) of 5-ethoxy-2-methyl-4-nitroacetanilide was added in one fraction. Continue to heat under reflux. After about 45 minutes (color of the permanganate disappears), 37.62 g of magnesium sulfate and 108.65 g of potassium permanganate are further added. After further refluxing (disappearance of the permanganate salt) for about 45 minutes, the reaction is filtered while hot. It holds a manganese dioxide cake. The filtrate is oxidized with concentrated hydrochloric acid to provide the product. The manganese dioxide retained is boiled with 2000 mL of water and then filtered. The filtrate is oxidized to provide additional product. The products are combined and dried to give 68.19 g (50.8%) of the desired product. The starting material can be extracted from manganese dioxide using acetone.
[1290] 3-ethoxy-4-nitryl aniline
[1291] Add 400 mL of concentrated H ₂ OSO ₄ to 600 mL of H ₂ O slowly. To the hot mixture was added 118.5 g (0.44 mol) of 2-acetylamino-4-ethoxy-5-nitro-benzoic acid. The mixture is heated to 110-112 &lt; 0 &gt; C with stirring. Initially, the gas is released violently. After 1 hour, the mixture is poured into ice. The mixture is made basic with concentrated ammonium hydroxide (exothermic reaction continues). The mixture is cooled to room temperature and the solids are collected by filtration. The solid was washed several times with water (500 mL), dried under vacuum, and then extracted several times with warm ethyl acetate. The residue is filtered off and the solvent is removed to give 57.8 g (71%) of product.
[1292] 2- (2-Cyano-2-ethoxycarbonyl-vinylamino) -4-ethoxy-5-nitro-
[1293] A mixture of 58.96 g (0.324 mol) of 3-ethoxy-4-nitroaniline and 77.22 g (0.456 mol) of ethyl (ethoxymethylene) in 210 mL of toluene is refluxed for about 16 hours (overnight). The reaction is cooled in an ice bath and the product is filtered. Washed three times with ether and dried to give 94.33 g (95.8%) of the desired product. Which can be recrystallized from methyl cellosolve in about 80% yield.
[1294] 7-Ethoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile
[1295] 2- (2-Cyano-2-ethoxycarbonyl-vinylamino) -4-ethoxy-5-nitro-benzoic acid (37.5 g, 0.123 mol), recrystallized from 2-methoxyethanol, Is added as a solid to 2.5 liters of Dawsam refluxed (256 DEG C) in a 5 L three-necked flask equipped with a mechanical stirrer and thermometer. The reaction mixture is vigorously stirred at this temperature for 1.25 hours and then cooled to room temperature. The thick reaction mixture was diluted with 2 L of ether, filtered and washed with ether to give 24.2 g (yield: &lt; RTI ID = 0.0 &gt; : 76%).
[1296] The filtrate is evaporated to remove the ether and then treated with hexane. The resulting yellow precipitate is collected and washed with hexane to yield 10-15% of unreacted starting material which can be recycled to produce a more circulated product. The resulting filtrate is evaporated to remove the hexane and passed through a thin silica gel pad to remove the colored impurities to further regenerate the douche for a more cyclic reaction.
[1297] Chloro-7-ethoxy-6-nitro-quinoline-3-carbonitrile
[1298] The nitro compound 7-ethoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile (20 g, 77 mmol) is refluxed in 120 mL of phosphorus oxychloride for 2.5 hours under nitrogen. TLC (ethyl acetate: hexane = 1: 1) indicates that no starting material remained. The volatile reagents are removed with a rotary evaporator and then further removed with an azeotropic mixture using toluene at 50 ° C. The flask containing the solid residue is cooled in an ice bath and then 600 mL of methylene chloride is added to dissolve the residue. The resulting cold methylene chloride solution is added to 250 mL (53.3 g, 5 eq.) Of vigorously stirred ice-cold potassium carbonate saturated solution and stirred for 30 minutes. The organic layer was separated, washed and then dried to give 18.58 g of 4-chloro-7-ethoxy-6-nitro-quinoline-3-carbonitrile (yield: 86.9%).
[1299] 4- (3-Chloro-4-fluoro-phenylamino) -7-ethoxy-6-nitro-quinoline-
[1300] (26.05 g, 96.5 mmol) and 3-chloro-4-fluoroaniline (14.05 g, 96.5 mmol) in 900 mL of iso-propanol were dissolved in N ₂ under reflux for 3.5 hours. TLC (ethyl acetate: hexane = 1: 1) indicates that no starting material remained. After standing overnight at room temperature the hydrochloride salt was filtered off and washed with isopropanol to give 4- (3-chloro-4-fluoro-phenylamino) -7-ethoxy-6-nitro- 38.6 g (95%) of 3-carbonitrile are obtained.
[1301] 6-Amino-4- (3-chloro-4-fluoro-phenylamino) -7-ethoxy-quinoline-
[1302] 6-nitro-quinoline-3-carbonitrile hydrochloride (38.6 g, 91.2 mmol) was mixed with 35.7 g (638 mmol) of iron powder do. A solution of 43.9 g (820 mmol) of ammonium chloride in 280 mL of water is added followed by 985 mL of methanol. The mixture is refluxed under mechanical stirring with nitrogen for 4 hours, the time at which TLC shows complete reduction. The reaction mixture is filtered while hot, and the solid is then washed with 500 mL of boiling methanol. After evaporation of the combined filtrate, the residue is partitioned between 1.5 L warm ethyl acetate and 700 mL saturated sodium bicarbonate. The organic layer was dried with magnesium sulfate, Norris Trojan treated, filtered, and evaporated, and the CHCl _3-solid recrystallized from hexane 6-Amino-4- (3-Chloro-4-fluoro-phenylamino) 29.0 g (89%) of 7-ethoxy-quinoline-3-cannonitrile are obtained as a light green solid.
[1303] Chloro-4-fluoro-phenylamino) -3-cyano-quinolin-6-yl] -amide
[1304] (69.5 mmol) of oxalyl chloride was added to 14.98 g (63.17 mmol) of trimethylsilyl 4-bromo-2-butenoate (Synthesis 745 1983) in 36 mL of methylene chloride followed by the addition of 1 drop of anhydrous DMF do. After stirring the solution for 2 hours, the solvent is evaporated and further azeotropically distilled with carbon tetrachloride to give the acid chloride.
[1305] A solution of 6-amino-4- (3-chloro-4-fluoro-phenylamino) -7-ethoxy-quinoline- (65.91 mmol) of diisopropylethylamine. The above prepared acid chloride solution in 183 mL of THF is added over 15 minutes and then stirred at 0 &lt; 0 &gt; C for 30 minutes. The reaction vessel is sealed and then stored overnight in the freezer.
[1306] The reaction solution is rotary evaporated, and the residue is partitioned between saturated sodium bicarbonate and ethyl acetate. The organic layer was separated, washed, dried over magnesium sulfate and then passed through a thin layer of silica gel to give 32 g of crude product as an orange solid. The crude product is refluxed with 400 mL of methanol for 30 min. After cooling to room temperature, the solid was collected, washed with methanol and then washed with hexane to give 21.3 g (yield: 76.5%) of a beige solid. A mixture of a bromo compound and a chloro compound. More product can be separated from the mother liquor.
[1307] Chloro-4-fluoro-phenylamino) -3-cyano-7-ethoxy-quinolin-6-yl] -amide
[1308] Bromo / chloro compound (19.88 g, 39.53 mmol) is dissolved in 800 mL THF at 0 &lt; 0 &gt; C and 2 equivalents of 2M dimethylamine (39.54 mL, 79.07 mmol) in THF are added in one portion. The reaction solution is stirred overnight at room temperature. Another equivalent amount of dimethylamine is added. After stirring overnight at room temperature, only 10% of the chloro compound does not react. The reaction solution is rotary evaporated, and the residue is partitioned between ethyl acetate and saturated potassium bicarbonate. The organic layer is dried, filtered and evaporated to give 17 g of an orange solid. The crude product is dissolved in acetone and then purified by column chromatography using acetone as an eluent. The main fraction was collected and evaporated to give 9.8 g of a yellow glass. It is then dissolved in 350 mL of hot ethyl acetate and then evaporated to a thick solution. A few drops of methanol are added to assist in recrystallization. After allowing to stand overnight at room temperature, the beige crystals were filtered off to give pure 4-dimethylamino-but-2-enoic acid 4 - [(3- chloro-4-fluoro-phenylamino) 6-yl] -amide (mp: 196-198 [deg.] C) in 38.7% yield. Many products remain in the mother liquor during the chromatography and recrystallization steps and can be separated. The expected yield is about 60%.

权利要求:
Claims (21)
[1" claim-type="Currently amended] A method of treating or inhibiting a colonic polyp of a mammal in need thereof, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need of treating or inhibiting a colonic polyp.
Formula I

In the formula (I)
X is cycloalkyl having 3 to 7 carbon atoms which may optionally be substituted with one or more alkyl of 1 to 6 carbon atoms, or a pyridinyl, pyrimidinyl or phenyl ring wherein the pyridinyl, pyrimidinyl or phenyl ring is optionally substituted with halogen, Alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, azido, hydroxyalkyl having 1 to 6 carbon atoms, halomethyl, alkoxymethyl having 2 to 7 carbon atoms, alkanoyl having 2 to 7 carbon atoms Carbonyl having 2 to 7 carbon atoms, carboalkyl having 2 to 7 carbon atoms, phenoxyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, alkylthio having 1 to 6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, Benzyl, benzyl, amino, alkylamino of 1 to 6 carbon atoms, diacylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, alkanoylamino of 3 carbon atoms Disubstituted or trisubstituted by a substituent selected from the group consisting of alkenoylamino of 1 to 8 carbon atoms, alkenoylamino of 1 to 8 carbon atoms, alkynoylamino of 1 to 8 carbon atoms, alkynoylamino of 1 to 8 carbon atoms, alkynoylamino of 1 to 8 carbon atoms,
n is 0 or 1;
Y is -NH-, -O-, -S- or -NR-;
R is alkyl having 1 to 6 carbon atoms;
R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, halogen, alkyl having 1 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, alkenyloxy having 2 to 6 carbon atoms , Alkynyloxy having 2 to 6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy having 1 to 6 carbon atoms, alkenoyloxy having 3 to 8 carbon atoms, alkynoyloxy having 3 to 8 carbon atoms, alkynoyloxy having 2 to 7 carbon atoms Alkanoyloxymethyl having 4 to 9 carbon atoms, alkanoyloxymethyl having 4 to 9 carbon atoms, alkoxymethyl having 2 to 7 carbon atoms, alkoxy having 1 to 6 carbon atoms, alkylthio having 1 to 6 carbon atoms, Alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonamide of 1 to 6 carbon atoms, alkenylsulfonamido of 2 to 6 carbon atoms, alkynylsulfonamido of 2 to 6 carbon atoms, hydroxy , Trifluoromethyl, cyano, nitro, carboxy, carbon Carboalkoxy having 2 to 7 carbon atoms, carbonyl having 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino having 1 to 4 carbon atoms, alkylamino having 1 to 6 carbon atoms, Alkylaminoalkyl of 2 to 12 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, N-alkylaminoalkyl of 2 to 7 carbon atoms, N, N-dialkylaminoalkyl of 3 to 14 carbon atoms, phenylamino,
, , , , , , , , , , , , , , , , or ego;
R ₅ is C 1 -C 6 alkyl, optionally with one or more halogen atoms substituted alkyl, phenyl, or one or more halogen, C 1 -C 6 alkoxy, trifluoromethyl, amino, nitro, cyano or C 1 -C 6, Phenyl optionally substituted with an alkyl group;
R ₆ is hydrogen, alkyl having 1 to 6 carbon atoms or alkenyl having 2 to 6 carbon atoms;
R &lt; ₇ &gt; is chloro or bromo;
R ₈ is selected from the group consisting of hydrogen, alkyl having 1 to 6 carbon atoms, aminoalkyl having 1 to 6 carbon atoms, N-alkylaminoalkyl having 2 to 9 carbon atoms, N, N-dialkylaminoalkyl having 3 to 12 carbon atoms, N-cycloalkylaminoalkyl, N-cycloalkyl-N-alkylaminoalkyl having 5 to 18 carbon atoms, N, N-dicycloalkylaminoalkyl having 7 to 18 carbon atoms, morpholino having 1 to 6 carbon atoms in the alkyl group -N-alkyl having 1 to 6 carbon atoms, piperidino-N-alkyl having 1 to 6 carbon atoms in the alkyl group, N-alkyl-piperidino-N-alkyl having 1 to 6 carbon atoms in the alkyl group, Alkyl, alkoxyalkyl of 2 to 8 carbons, carboxy, carboalkoxy of 1 to 6 carbons, phenyl, carbamoyl of 2 to 7 carbons, chloro, fluoro or bromo ;
Z is amino, hydroxy, alkoxy having 1 to 6 carbon atoms, alkylamino having 1 to 6 carbon atoms in the alkyl moiety, dialkylamino having 1 to 6 carbon atoms in each alkyl moiety, morpholino, piperazino, alkyl Alkylpiperazino or pyrrolidino having 1 to 6 carbon atoms in the residue;
m is from 1 to 4;
q is 1 to 3;
p is from 0 to 3;
Adjacent substituent located at the carbon atom to R _1, R _2, R ₃ or R ₄ is taken together divalent be a radical -OC (R _{8) 2} -O-,
Provided that when Y is -NH-, R ₁ , R ₂ , R ₃ and R ₄ are hydrogen,
When n is 0, X is not 2-methylphenyl.
[2" claim-type="Currently amended] The method according to claim 1, wherein Y is -NH- and n is 0, or a pharmaceutically acceptable salt thereof.
[3" claim-type="Currently amended] 3. A method according to claim 2 wherein X is optionally substituted phenyl or a pharmaceutically acceptable salt thereof.
[4" claim-type="Currently amended] 4. The method according to claim 3, wherein R ₁ and R ₄ are hydrogen or a pharmaceutically acceptable salt thereof.
[5" claim-type="Currently amended] The method of claim 1, wherein 4 - [(3-bromophenyl) amino] -6,7-diethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof is provided.
[6" claim-type="Currently amended] 4. The compound of claim 1 which is 4-dimethylamino-but-2-enoic acid 4 - [(3-chloro-4-fluoro-phenylamino) -3- cyano-7-methoxy-quinolin- - amide or a pharmaceutically acceptable salt thereof.
[7" claim-type="Currently amended] 4. The compound of claim 1 which is 4-diethylamino-but-2-enoic acid 4 - [(3-chloro-4-fluoro-phenylamino) -3- cyano-7-methoxy-quinolin- ] -Amide or a pharmaceutically acceptable salt thereof.
[8" claim-type="Currently amended] 4. The compound of claim 1 which is 4-dimethylamino-but-2-enoic acid 4 - [(3-bromo-4-fluoro-phenylamino) -3- cyano-7-methoxy-quinolin- ] -Amide or a pharmaceutically acceptable salt thereof.
[9" claim-type="Currently amended] 4. The compound of claim 1 which is 4-dimethylamino-but-2-enoic acid 4 - [(3-bromo-phenylamino) -3-cyano-7-ethoxy-quinolin- Or a pharmaceutically acceptable salt thereof.
[10" claim-type="Currently amended] 4. The compound of claim 1 which is 4-diethylamino-but-2-enoic acid 4 - [(3-bromo-phenylamino) -3- cyano-7-ethoxy-quinolin- Wherein a pharmaceutically acceptable salt thereof is provided.
[11" claim-type="Currently amended] 4. The compound of claim 1 which is 4-morpholin-4-yl-but-2-enoic acid 4 - [(3-chloro-4-fluoro-phenylamino) -3- cyano- 6-yl] -amide or a pharmaceutically acceptable salt thereof.
[12" claim-type="Currently amended] 6. The compound of claim 1 which is 4-dimethylamino-but-2-enoic acid 4 - [(3-bromo-phenylamino) -3-cyano-7-methoxy-quinolin- Or a pharmaceutically acceptable salt thereof.
[13" claim-type="Currently amended] 4. The compound of claim 1 which is N- [4- (3-bromophenyl) amino] -3-cyano-6-quinoline] -4-methoxy-2-butynamide or a pharmaceutically acceptable salt thereof How to do it.
[14" claim-type="Currently amended] 2. The compound according to claim 1, which is N- {4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -4- &Lt; / RTI &gt;
[15" claim-type="Currently amended] 7. The compound of claim 1 which is 4-dimethylamino-but-2-enoic acid 4 - [(3-chloro-4-fluoro-phenylamino) -3- cyano-7-ethoxy-quinolin- - amide or a pharmaceutically acceptable salt thereof.
[16" claim-type="Currently amended] The method according to claim 1,
a) 4 - [(3-Bromophenyl) amino] -7-methoxy-3-quinolinecarbonitrile;
b) 4 - [(3-Bromophenyl) amino] -7-methoxy-6-nitro-3-quinolinecarbonitrile;
c) 6-Amino-4 - [(3-bromophenyl) amino] -7-methoxy-3-quinolinecarbonitrile;
d) N- [4 - [(3-bromophenyl) amino] -3-cyano-7-methoxy-6-quinolinyl] -2-butynamide;
e) N- [4 - [(3-bromophenyl) amino] -3-cyano-7-methoxy-6-quinolinyl] -2-propenamide;
f) 4 - [(3-bromophenyl) amino] -6-nitro-3-quinolinecarbonitrile;
g) 6-Amino-4 - [(3-bromophenyl) amino] -3-quinolinecarbonitrile;
h) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -2-butynamide;
i) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] acetamide;
j) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] butanamide;
k) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -2-propenamide;
l) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -2-chloroacetamide;
m) 4 - [(3,4-dibromophenyl) amino] -6-nitro-3-quinolinecarbonitrile;
n) 6-Amino-4 - [(3,4-dibromophenyl) amino] -3-quinolinecarbonitrile;
o) N- [4 - [(3,4-dibromophenyl) amino] -3-cyano-6-quinolinyl] -2-butynamide;
p) 6-Nitro-4 - [(3-trifluoromethylphenyl) amino] -3-quinolinecarbonitrile;
q) 6-Amino-4 - [(3-trifluoromethylphenyl) amino] -3-quinolinecarbonitrile;
r) N- [4 - [(3-Trifluoromethylphenyl) amino] -3-cyano-6-quinolinyl] -2-butynamide;
s) 4 - [(3-bromophenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile;
t) 4 - [(3-fluorophenyl) amino] -6, 7-dimethoxy-3-quinolinecarbonitrile;
u) 4- (Cyanohexylamino) -6,7-dimethoxy-3-quinolinecarbonitrile;
v) 4 - [(3-bromophenyl) amino] -6,7-dihydroxy-3-quinolinecarbonitrile;
w) 8 - [(3-Bromophenyl) amino] - [1,3] -dioxolo [4,5-g] quinoline-7-carbonitrile;
x) 4 - [(3-chlorophenyl) amino] -6, 7-dimethoxy-3-quinolinecarbonitrile;
y) 4 - [(3-Trifluoromethylphenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile;
z) 4 - [(3,4-dimethoxyphenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile;
aa) 4 - [(methylphenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile;
bb) 4 - [(3-cyanophenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile;
cc) 4 - [(4-fluorophenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile;
dd) 4 - [(3- (hydroxymethyl) phenyl) amino] -6, 7-dimethoxy-3-quinolinecarbonitrile;
ee) 4- (3-Bromophenoxy) -6, 7-dimethoxy-3-quinolinecarbonitrile;
ff) 4 - [(4-Bromophenyl) sulfanyl] -6, 7-dimethoxy-3-quinolinecarbonitrile;
gg) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -3 (E) -chloro-2-propenamide;
hh) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -3 (Z) -chloro-2-propenamide;
ii) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -2-methyl-2-propenamide;
jj) N- [4 - [(3,4-dibromophenyl) amino] -3-cyano-6-quinolinyl] -2-propenamide;
kk) N- [4 - [(5-bromo-3-pyridinyl) amino] -6, 7-dimethoxy-3-quinolinecarbonitrile;
ll) 4 - [(3-bromophenyl) amino] -6,7-bis (methoxymethoxy) -3-quinolinecarbonitrile;
mm) N-4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-hydroxy-2-butynamide;
nn) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-morpholino-2-butynamide;
oo) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-dimethylamino-2-butynamide;
pp) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-methoxy-2-butynamide;
qq) 4- (3-bromophenylmethylamino) -6,7-diethoxy-3-quinolinecarbonitrile;
rr) 4- (3-Phenylmethylamino) -6, 7-diethoxy-3-quinolinecarbonitrile;
ss) 4- (3,4-dimethoxyphenylmethylamino) -6,7-diethoxy-3-quinolinecarbonitrile;
tt) 4- (3,4-Dichlorophenylmethylamino) -6,7-diethoxy-3-quinolinecarbonitrile;
uu) 4-Methoxy-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-quinolin-6-yl] -amide;
vv) 4- (4-Chloro-2-fluoro-phenylamino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile;
ww) 4- (4-Chloro-2-fluoro-phenylamino) -6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinoline-3-carbonitrile;
xx) 7- (2-Dimethylamino-ethoxy) -4- (3-hydroxy-4-methyl-phenylamino) -6-methoxy-quinoline-3-carbonitrile;
yy) 4- (3-Hydroxy-4-methyl-phenylamino) -6-methoxy- 7- (2-morpholin-4-yl-ethoxy) -quinoline-
zz) 4- (4-Chloro-2-fluoro-5-hydroxy-phenylamino) -7- (3-dimethylamino-propoxy) -6-methoxy-quinoline-3-carbonitrile; Or a pharmaceutically acceptable salt thereof.
[17" claim-type="Currently amended] The method according to claim 1,
a) 4- (4-Chloro-2-fluoro-5-hydroxy-phenylamino) -6-methoxy- 7- (3-morpholin- ;
b) 4- (4-Chloro-2-fluoro-5-hydroxy-phenylamino) -7- (2-dimethylamino-ethoxy) -6-methoxy-quinoline-3-carbonitrile;
c) 4- (4-Chloro-2-fluoro-5-hydroxy-phenylamino) -6-methoxy- 7- (2-morpholin-4-yl-ethoxy) -quinoline- ;
d) N- [3-cyano-4- (3-fluorophenylamino) quinolin-6-yl] acrylamide;
e) 6,7-Dimethoxy-4- (3-nitrophenylamino) quinolin-3-carbonitrile;
f) 4- (3-Bromophenylamino) -6-ethoxy-7-methoxyquinoline-3-carbonitrile;
g) 6-Ethoxy-4- (3-hydroxy-4-methylphenylamino) -7-methoxyquinoline-3-carbonitrile;
h) 4-Dimethylamino-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-quinolin-6-yl] -amide;
i) 4-Diethylamino-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-quinolin-6-yl] -amide;
j) 4-Methylamino-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-quinolin-6-yl] -amide;
k) 4 - [(3-bromophenyl) amino] -8-methyl-6-nitro-3-quinolinecarbonitrile;
l) 4 - [(3-bromophenyl) amino] -8-dimethylaminomethyl-6-nitro-3-quinolinecarbonitrile;
m) 6-Amino-4 - [(3-bromophenyl) amino] -8-dimethylaminomethyl-3-quinolinecarbonitrile;
n) N- {4 - [(3-bromophenyl) amino] -3-cyano-8-dimethylaminomethyl-6-quinolinyl} -2-butynamide;
o) N- {4 - [(3-bromophenyl) amino] -3-cyano-8-dimethylaminomethyl-6-quinolinyl} -2-propenamide;
p) N- {4 - [(3-bromophenyl) amino] -3-cyano-8-dimethylaminomethyl-6-quinolinyl} acetamide;
q) 4 - [(3-chloro-4-fluorophenyl) amino] -7-methoxy-6- (morpholinoproxy) -3-quinolinecarbonitrile;
r) 4 - [(3-bromophenyl) amino] -7-methoxy-6- (morpholinoproxy) -3-quinolinecarbonitrile;
s) 4 - [(4-chloro-2-fluorophenyl) amino] -7-methoxy-6- (morpholinopropoxy) -3-quinolinecarbonitrile;
t) 4 - [(3-hydroxy-4-methylphenyl) amino] -7-methoxy-6- (morpholinopropoxy) -3-quinolinecarbonitrile;
u) N- {3-cyano-4 - [(3-iodophenyl) amino] -6-quinolinyl} -2-propenamide;
v) 6-Amino-4 - [(3-iodophenyl) amino] -3-quinolinecarbonitrile;
w) 4 - [(3-iodophenyl) amino] -6-nitro-3-quinolinecarbonitrile;
x) N- {3-Cyano-4 - [(3-methylphenyl) amino] -6-quinolinyl} -2-butynamide;
y) 6-Amino-4 - [(3-methylphenyl) amino] -3-quinolinecarbonitrile;
z) 6-Nitro-4 - [(3-methylphenyl) amino] -3-quinolinecarbonitrile;
aa) N- {4 - [(3-chlorophenyl) amino] -3-cyano-6-quinolinyl} -2-propenamide;
bb) 6-Amino-4 - [(3-chlorophenyl) amino] -3-quinolinecarbonitrile;
cc) 4 - [(3-chlorophenyl) amino] -6-nitro-3-quinolinecarbonitrile;
dd) N- {3-Cyano-4 - [(3-methoxyphenyl) amino] -6-quinolinyl} -2-propenamide;
ee) N- {3-Cyano-4 - [(3-methoxyphenyl) amino] -6-quinolinyl} -2-butynamide;
ff) N- {3-cyano-4 - [(3-methoxyphenyl) amino] -6-quinolinyl} -4-piperidino-2-butynamide;
gg) 6-Amino-4 - [(3-methoxyphenyl) amino] -3-quinolinecarbonitrile;
hh) 4 - [(3-methoxyphenyl) amino] -6-nitro-3-quinolinecarbonitrile;
ii) N- {4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -2-butynamide;
jj) N- {4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -2-propenamide;
kk) N- {4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -4-diethylamino-2-butenamide;
ll) N- {4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -4-morpholino-2-butenamide;
mm) N- {4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -2-morpholin-4-ylmethyl-2-propenamide;
nn) 6-Amino-4 - [(3-chloro-4-fluorophenyl) amino] -3-quinolinecarbonitrile;
oo) 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-3-quinolinecarbonitrile;
pp) N- {4 - [(4-bromophenyl) amino] -3-cyano-6-quinolinyl} -2-propenamide;
qq) 6-Amino-4 - [(4-bromophenyl) amino] -3-quinolinecarbonitrile;
rr) [(4-bromophenyl) amino] -6-nitro-3-quinolinecarbonitrile;
ss) N- {3-cyano-4 - [(3,4-difluorophenyl) amino) -6-quinolinyl] -2-propenamide;
tt) 6-Amino-4 - [(3,4-difluorophenyl) amino] -3-quinolinecarbonitrile;
uu) 4 - [(3,4-difluorophenyl) amino] -6-nitro-3-quinolinecarbonitrile;
ww) N- {4 - [(3-chloro-4-thiophenoxyphenyl) amino] -3-cyano-6-quinolinyl} -2-butynamide;
xx) 6-Amino-4 - [(3-chloro-4-thiophenoxyphenyl) amino] -3-quinolinecarbonitrile;
yy) 4 - [(3-chloro-4-thiophenoxyphenyl) amino] -6-nitro-3-quinolinecarbonitrile or
zz) N- {3-cyano-4 - [(3-cyanophenyl) amino] -6-quinolinyl} -2-propenamide; Or a pharmaceutically acceptable salt thereof.
[18" claim-type="Currently amended] The method according to claim 1,
a) N- {3-Cyano-4 - [(3-cyanophenyl) amino] -6-quinolinyl} -4-piperidino-2-butynamide;
b) 6-Amino-4 - [(3-cyanophenyl) amino] -3-quinolinecarbonitrile;
c) 4 - [(3-cyanophenyl) amino] -6-nitro-3-quinolinecarbonitrile;
d) N- {3-Cyano-4 - [(3-ethynylphenyl) amino] -6-quinolinyl} -2-butynamide;
e) N- {3-Cyano-4 - [(3-ethynylphenyl) amino] -6-quinolinyl} -2-propenamide;
f) N- {3-Cyano-4 - [(3-ethynylphenyl) amino] -6-quinolinyl} -4-piperidino-2-butynamide;
g) 6-Amino-4 - [(3-ethynylphenyl) amino] -3-quinolinecarbonitrile;
h) 4 - [(3-ethynylphenyl) amino] -6-nitro-3-quinolinecarbonitrile;
i) N- {4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl} -4-piperidino-2-butynamide;
j) N- {4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl} -4-dipropylamino-2-butynamide;
k) N- {4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl} -2-morpholin-4-ylmethyl-2-propenamide;
l) N- {4 - [(3-Bromo-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -4-dimethylamino-2-butenamide;
m) N- {4 - [(3-bromo-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -4-diethylamino-2-butenamide;
n) N- {4 - [(3-bromo-4-fluorophenyl) amino] -3-cyano-6-quinolinyl} -4-morpholino-2-butenamide;
o) N- {4 - [(3-Bromo-4-fluorophenyl) amino] -3-cyano-7-methoxy-6-quinolinyl} -4-morpholino- ;
p) 4 - [(3-bromophenyl) amino] -7-ethoxy-6-methoxy-3-quinolinecarbonitrile;
q) 7-Ethoxy-4 - [(3-hydroxy-4-methylphenyl) amino] -6-methoxy-3-quinolinecarbonitrile;
r) N- [4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl] -4-dimethylamino- (z) -2-butenamide;
s) N- [4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl] -4-methoxy- (z) -2-butenamide;
t) 4 - [[4- (3-bromophenyl) amino] -3-cyano-6-quinolinyl] amino] -2-methylene-4-oxo-butanoic acid;
u) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-diethylamino-2-butynamide;
v) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4- (n-ethylpiperazino) -2-butynamide;
w) N- [4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl] -4-diethylamino-2-butynamide;
x) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4- (n-methylpiperazino) -2-butynamide;
y) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4- (n-isopropyl-n-methylamino) -2-butynamide;
z) N- [4 - [(3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-diisopropylamino-2-butynamide;
aa) N- [4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl] -4-dimethylamino-2-butynamide;
bb) N- [4 - [(3-chloro-4-fluorophenyl) amino] -3-cyano-6-quinolinyl] -4-methoxy-2-butynamide;
cc) 4 - [(3-Bromo-4-fluorophenyl) amino] -6-nitro-3-quinolinecarbonitrile;
dd) 6-Amino-4 - [(3-bromo-4-fluorophenyl) amino] -3-quinolinecarbonitrile;
ee) N- [4 - [(3-bromo-4-fluorophenyl) amino] -3-cyano-6-quinolinyl] -4-dimethylamino-2-butynamide;
ff) 4-Diethylamino-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide;
gg) 4-Morpholin-4-yl-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide;
hh) 4- (3-Chloro-4-fluoro-phenylamino) -7-methoxy-6-nitro-quinoline-3-carbonitrile;
ii) 6-Amino-4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-quinoline-3-carbonitrile;
jj) 4- (3-Bromo-4-fluoro-phenylamino) -7-methoxy-6-nitro-quinoline-3-carbonitrile;
kk) 6-Amino-4- (3-bromo-4-fluoro-phenylamino) -7-methoxy-quinoline-3-carbonitrile;
ll) 4-Diethylamino-but-2-enoic acid [4- (3-bromo-4-fluoro-phenylamino) -3- cyano-7-methoxy-quinolin- ;
mm) 4- (3-Bromo-phenylamino) -7-ethoxy-6-nitro-quinoline-3-carbonitrile;
nn) 6-Amino-4- (3-bromo-phenylamino) -7-ethoxy-quinoline-3-carbonitrile;
oo) 4-Bromo-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-7-ethoxy-quinolin-6-yl] -amide;
pp) 4-Morpholin-4-yl-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-7-ethoxy-quinolin-6-yl] -amide;
qq) 6-Amino-4- (3-bromo-phenylamino) -8-methoxy-quinoline-3-carbonitrile;
rr) 6-Amino-4- (3-bromo-phenylamino) -8-methoxy-quinoline-3-carbonitrile;
ss 4-Bromo-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-8-methoxy-quinolin-6-yl] -amide;
tt) 4-Dimethylamino-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-8-methoxy-quinolin-6-yl] -amide;
uu) 4-Diethylamino-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-8-methoxy-quinolin-6-yl] -amide;
vv) 4-Morpholin-4-yl-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-8-methoxy-quinolin-6-yl] -amide;
ww) 4-Dimethylamino-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide;
xx) 4- (4-Chloro-2-fluoro-phenylamino-6,7-dimethoxy-quinolin-3-carbonitrile;
yy) 4- (3-Hydroxy-4-methyl-phenylamino-6,7-dimethoxy-quinolin-3-carbonitrile or
zz) 4- (3-Dimethylamino-phenylamino) -6,7,8-trimethoxy-quinoline-3-carbonitrile; Or a pharmaceutically acceptable salt thereof.
[19" claim-type="Currently amended] The method according to claim 1,
a) 4- (3-Hydroxy-4-methyl-phenylamino) -6,7,8-trimethoxy-quinoline-3-carbonitrile;
b) 4- (4-Chloro-2-fluoro-phenylamino) -6,7,8-trimethoxy-quinoline-3-carbonitrile;
c) 4- (4-Chloro-2-fluoro-phenylamino) -5,8-dimethoxy-quinolin-3-carbonitrile;
d) 4- (3-Hydroxy-4-methyl-phenylamino) -5,8-dimethoxy-quinolin-3-carbonitrile;
e) 4- (3-Bromo-phenylamino) -5,8-dimethoxy-quinoline-3-carbonitrile;
f) 4- (3-Bromo-phenylamino) -6,7,8-trimethoxy-quinoline-3-carbonitrile;
g) 4- (3-Dimethylamino-phenylamino) -5,8-dimethoxy-quinolin-3-carbonitrile;
h) 4- (4-Chloro-2-fluoro-5-hydroxy-phenylamino) -5,8-dimethoxy-quinolin-3-carbonitrile;
i) 4- (4-Chloro-2-fluoro-5-hydroxy-phenylamino) -6,7,8-trimethoxy-quinoline-3-carbonitrile;
j) 4- (3-Hydroxy-2-methyl-phenylamino) -6,7-dimethoxy-quinolin-3-carbonitrile;
k) 4- (2-Hydroxy-6-methyl-phenylamino) -6,7-dimethoxy-quinolin-3-carbonitrile;
l) 4- (3-Bromo-4-methyl-phenylamino) -6, 7-dimethoxy-quinolin-3-carbonitrile;
m) 4- (3-Chloro-4-hydroxy-phenylamino) -6, 7-dimethoxy-quinolin-3-carbonitrile;
n) 6,7-Dimethoxy-4- (2-methylsulfanyl-phenylamino) -quinoline-3-carbonitrile;
o) 1,4-Dihydroquinoline-6,7-diethoxy-4-oxo-3-carbonitrile;
p) 4- [3-chloro-4- (phenylthio) phenylamino] -6,7-diethoxy-3-quinolinecarbonitrile;
q) 4- [3-chloro-4- (phenylthio) phenylamino] -6,7-dimethoxy-3-quinolinecarbonitrile;
r) 4- (3-Chloro-4-fluorophenylamino) -6,7-diethoxy-3-quinolinecarbonitrile;
s) 4- (3-acetylphenylamino) -6,7-diethoxy-3-quinolinecarbonitrile;
t) 4- (n-methylphenylamino) -6, 7-diethoxy-3-quinolinecarbonitrile;
u) 4- (phenylamino) -6, 7-diethoxy-3-quinolinecarbonitrile;
v) 4- (4-fluorophenylamino) -6, 7-diethoxy-3-quinolinecarbonitrile;
w) 4- (4-Fluoro-2-methylphenylamino) -6, 7-diethoxy-3-quinolinecarbonitrile;
x) 4- (3-chlorophenylamino) -6, 7-diethoxy-3-quinolinecarbonitrile;
y) 4- (3-fluorophenylamino) -6, 7-diethoxy-3-quinolinecarbonitrile;
z) 4- (3-aminophenylamino) -6,7-dimethoxy-3-quinolinecarbonitrile;
aa) 4- (3-Acetamidophenylamino) -6,7-dimethoxy-3-quinolinecarbonitrile;
bb) 4- [3- (2-Butynoylamino) phenylamino] -6,7-dimethoxy-3-quinolinecarbonitrile;
cc) 4- [3- (hydroxymethyl) phenylamino] -6, 7-dimethoxy-3-quinolinecarbonitrile;
dd) 4- [3- (chloromethyl) phenylamino] -6,7-dimethoxy-3-quinolinecarbonitrile;
ee) 4- [3- (acetylthiomethyl) phenylamino] -6,7-dimethoxy-3-quinolinecarbonitrile;
ff) 4- [3- (thiomethyl) phenylamino] -6,7-dimethoxy-3-quinolinecarbonitrile;
gg) 4 - [(3-bromophenyl) amino] -8-methoxy-3-quinolinecarbonitrile;
hh) 4- (4-Chloro-2-fluoro-phenylamino) -8-methoxy-quinoline-3-carbonitrile;
ii) 4- (3-Hydroxy-4-methyl-phenylamino) -8-methoxy-quinoline-3-carbonitrile;
jj) 4- (3-Dimethylamino-phenylamino) -8-methoxy-quinolin-3-carbonitrile;
kk) 4- (4-Bromo-3-hydroxy-phenylamino) -8-methoxy-quinoline-3-carbonitrile;
ll) 4- (3-Hydroxy-4-methoxy-phenylamino) -8-methoxy-quinolin-3-carbonitrile;
mm) 8-Methoxy-4- (2,4,6-trifluoro-phenylamino) -quinoline-3-carbonitrile;
nn) 4- (3-Hydroxy-4-methyl-phenylamino) -7-methoxy-quinoline-3-carbonitrile;
oo) 4- (4-Chloro-2-fluoro-5-hydroxy-phenylamino) -7-methoxy-quinolin-3-carbonitrile;
pp) 4- (4-Chloro-2-fluoro-phenylamino) -6-methoxy-quinolin-3-carbonitrile;
qq) 4- (3-Hydroxy-4-methyl-phenylamino) -6-methoxy-quinoline-3-carbonitrile;
rr) 4- (4-Chloro-2-fluoro-5-hydroxy-phenylamino) -6-methoxy-quinolin-3-carbonitrile;
ss) 4- (3,5-Dichloro-4-hydroxy-phenylamino) -6,7-dimethoxy-quinolin-3-carbonitrile;
tt) 4- (2-Hydroxy-4-methyl-phenylamino) -6,7-dimethoxy-quinolin-3-carbonitrile;
uu) 4- (4-hydroxy-3,5-dimethyl-phenylamino) -6,7-dimethoxy-quinoline-3-carbonitrile;
vv) 4- (5-Chloro-2-hydroxy-phenylamino) -6,7-dimethoxy-quinolin-3-carbonitrile;
ww) 4- (3,5-Dibromo-4-hydroxy-phenylamino) -6,7-dimethoxy-quinoline-3-carbonitrile;
xx) 4- (4-Hydroxy-2-methyl-phenylamino) -6,7-dimethoxy-quinoline-3-carbonitrile;
yy) 6,7-Dimethoxy-4- (pyridin-3-ylamino) -quinoline-3-carbonitrile or
zz) 6,7-Dimethoxy-4- (3-methylsulfanyl-phenylamino) -quinoline-3-carbonitrile; Or a pharmaceutically acceptable salt thereof.
[20" claim-type="Currently amended] The method according to claim 1,
a) 4- (2-Hydroxy-5-methyl-phenylamino) -6,7-dimethoxy-quinolin-3-carbonitrile;
b) 4- (2-Chloro-4-hydroxy-phenylamino) -6, 7-dimethoxy-quinolin-3-carbonitrile;
c) 6,7-Dimethoxy-4- (4-methylsulfanyl-phenylamino) -quinoline-3-carbonitrile;
d) 4- [4- (2-Hydroxy-ethyl) -phenylamino] -6,7-dimethoxy-quinoline-3-carbonitrile;
e) 4- (2,4-Dihydroxy-phenylamino) -6,7-dimethoxy-quinolin-3-carbonitrile;
f) 4- [2- (2-Hydroxy-ethyl) -phenylamino] -6,7-dimethoxy-quinoline-3-carbonitrile;
g) 4- (3-bromophenylamino) -6,7-dihydroxy-3-quinolinecarbonitrile;
h) 4- (3-bromophenylamino) -6,7-di-n-propoxy-3-quinolinecarbonitrile;
i) 4 - [(3-Bromophenyl) -n-acetylamino] -6, 7-dihydroxy-3-quinolinecarbonitrile;
j) 4- (3-bromophenylamino) -6,7-di-n-butoxy-3-quinolinecarbonitrile;
k) 4- (4-chloro-2-fluorophenylamino) -7-methoxy-3-quinolinecarbonitrile;
l) 4- (4-Chloro-2-fluorophenylamino) -7-hydroxy-3-quinolinecarbonitrile;
m) 4 - [(4-Chloro-2-fluorophenylamino) -n-acetylamino] -7-hydroxy-3-quinolinecarbonitrile;
n) 4- (4-chloro-2-fluorophenylamino) -7-ethoxy-3-quinolinecarbonitrile;
o) 4 - [(3-bromophenyl) amino] -6,7-bis (2-methoxyethoxy) -3-quinolinecarbonitrile;
p) 4- (2-aminophenylmethylamino) -6,7-diethoxy-3-quinolinecarbonitrile;
q) 4- (3,4-difluorophenylmethylamino) -6,7-diethoxy-3-quinolinecarbonitrile;
r) 4-Methoxy-but-2-enoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl] -amide;
s) 7-Benzyloxy-4- (4-chloro-2-fluoro-phenylamino) -6-methoxy-quinoline-3-carbonitrile;
t) 4- (4-Chloro-2-fluoro-5-hydroxy-phenylamino) -7-methoxy-6- (3- morpholin- ;
u) N- [4- (3-Bromo-phenylamino) -3-cyano-quinolin-6-yl] -3-chloro- (e) -acrylamide;
v) N- [4- (3-Bromo-phenylamino) -3-cyano-quinolin-6-yl] -3-chloro- (z) -acrylamide;
w) N- [4- (3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-morpholin-2-butynamide;
x) N- [4- (3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-dimethylamino-2-butynamide;
y) N- [4- (3-bromophenyl) amino] -3-cyano-6-quinolinyl] -4-t-butyldimethylsiloxy-2-butynamide;
z) N- [4- (3-bromophenyl) amino) -3-cyano-quinolinyl] -4-hydroxy-2-butynamide;
aa) 4- (3-hydroxymethyl-2-methylphenylamino) -6,7-dimethoxyquinoline-3-carbonitrile;
bb) 4- (2-amino-4,5-dimethylphenylamino) -6,7-dimethoxyquinoline-3-carbonitrile;
cc) 4- (4-ethylphenylamino) -6,7-dimethoxyquinoline-3-carbonitrile;
dd) 4- (4-chloro-2-methylphenylamino) -6,7-dimethoxyquinoline-3-carbonitrile;
ee) 6,7-Dimethoxy-4- (3-phenoxyphenylamino) -quinoline-3-carbonitrile;
ff) 4- (4-Chloro-3-trifluoromethylphenylamino) -6,7-dimethoxyquinoline-3-carbonitrile;
gg) 4- (3-hydroxy-phenylamino) -6, 7-dimethoxy-quinolin-3-carbonitrile;
hh) 4- (4-methyl-phenylamino) -6,7-dimethoxy-quinolin-3-carbonitrile;
ii) 4- (3-Hydroxy-4-methyl-phenylamino) -8-methoxy-6-nitro-quinoline-3-carbonitrile;
jj) 4- (4-Chloro-2-fluoro-phenylamino) -8-methoxy-6-nitro-quinoline-3-carbonitrile;
kk) 4- (3-hydroxy-4-methoxy-phenylamino) -8-methoxy-6-nitro-quinoline-3-carbonitrile;
ll) 6-Amino-4- (3-hydroxy-4-methyl-phenylamino) -8-methoxy-quinoline-3-carbonitrile;
mm) 6-Amino-4- (3-hydroxy-4-methoxy-phenylamino) -8-methoxy-quinoline-3-carbonitrile;
nn) N- {4 - [(3-bromo-4-fluorophenyl) amino] -3-cyano-7-methoxy-6-quinolinyl} -4-bromo-2-butenamide;
oo) N- {4 - [(3-bromophenyl) amino] -3-cyano-7-methoxy-6-quinolinyl} -4-chloro-2-butenamide;
pp) N- {3-cyano-4 - [(3-iodophenyl) amino] -6-quinolinyl} -2-butynamide;
qq) N- {3-cyano-4 - [(3-methylphenyl) amino] -6-quinolinyl} -2-propenamide;
rr) N- {4 - [(4-bromophenyl) amino] -3-cyano-6-quinolinyl} -2-butynamide;
ss) N- {4 - [(3-chloro-4-thiophenoxyphenyl) amino] -3-cyano-6-quinolinyl} -2-propenamide;
tt) N- {3-Cyano-4 - [(3,4-difluorophenyl) amino] -6-quinolinyl} -2-butynamide;
uu) N- {4 - [(3-chlorophenyl) amino] -3-cyano-6-quinolinyl} -2-butynamide;
vv) N- {3-cyano-4 - [(3-isopropylphenyl) amino] -6-quinolinyl} -2-butynamide;
ww) N- {3-Cyano-4 - [(3-isopropylphenyl) amino] -6-quinolinyl} -2-propenamide;
xx) 6-Amino-4 - [(3-isopropylphenyl) amino] -3-quinolinecarbonitrile;
yy) 4 - [(3-isopropylphenyl) amino] -6-nitro-3-quinolinylcarbonitrile or
zz) 4- (3-Bromo-phenylamino) -6- (3-pyrrolidin-1-yl-propylamino) -quinoline-3-carbonitrile; Or a pharmaceutically acceptable salt thereof.
[21" claim-type="Currently amended] The method according to claim 1,
a) 4- (3-Azido-phenylamino) -6,7-dimethoxy-quinolin-3-carbonitrile;
b) 6-Amino-4 - [(4-chloro-2-fluorophenyl) amino] -7-methoxy-3-quinolinecarbonitrile;
c) 4 - [(4-Chloro-2-fluorophenyl) amino] -7-methoxy-6-nitro-3-quinolinecarbonitrile;
d) 4 - [(3,4-dichlorophenyl) amino] -6-nitro-3-quinolinecarbonitrile;
e) 6-Amino-4 - [(3-methylsulfanylphenyl) amino] -3-quinolinecarbonitrile;
f) 4 - [(3-methylsulfanylphenyl) amino] -6-nitro-3-quinolinecarbonitrile;
g) 4 - [(3-Trifluoromethoxyphenyl) amino] -6-nitro-3-quinolinecarbonitrile;
h) 4- (3-Dimethylamino-phenylamino) -6,7-dimethoxy-quinoline-3-carbonitrile;
i) 6,7-Dimethoxy-4- (4-methoxy-2-methyl-phenylamino) -quinoline-3-carbonitrile;
j) 4- (3-Hydroxy-4-methoxy-phenylamino) -6, 7-dimethoxy-quinolin-3-carbonitrile;
k) 4- (3-Chloro-4-methyl-phenylamino) -6,7-dimethoxy-quinolin-3-carbonitrile;
l) 6,7-Dimethoxy-4- (4-phenoxy-phenylamino) -quinoline-3-carbonitrile;
m) 4- (5-Chloro-2-methoxy-phenylamino) -6,7-dimethoxy-quinoline-3-carbonitrile;
n) 3- (3-Cyano-6, 7-dimethoxy-quinolin-4-ylamino) -2-methyl-benzoic acid;
o) 4- (4-Chloro-2-fluoro-phenylamino) -6,7-dihydroxy-quinoline-3-carbonitrile;
p) 4- (3-Hydroxy-2-methyl-phenylamino) -6,7-dimethoxy-quinolin-3-carbonitrile;
q) 4- (3-Chloro-4-methoxy-phenylmethylamino) -6, 7-dimethoxy-quinolin-3-carbonitrile;
r) 6,7-Dimethoxy-4- (4-trifluoromethyl-phenylamino) -quinoline-3-carbonitrile;
s) 4- (3,4-dibromophenylamino) -6-nitroquinolin-3-carbonitrile;
t) 6-Amino-4- (3-trifluoromethylphenylamino) quinolin-3-carbonitrile;
u) 6-Amino-4- (3,4-dibromophenylamino) quinolin-3-carbonitrile;
v) N- [3-cyano-4- (3,4-dibromophenylamino) quinolin-6-yl] acrylamide;
w) N- [4- (3-bromophenylamino) -3-cyanoquinolin-6-yl] propionamide;
x) (e) -but-2-enoic acid [4- (3-bromophenylamino) -3-cyanoquinolin-6-yl] amide;
y) N- [4- (3-bromophenylamino) -3-cyanoquinolin-6-yl] -2-methylacrylamide;
z) 4- (3-fluorophenylamino) -6-nitroquinolin-3-carbonitrile;
aa) 6-Amino-4- (3-fluorophenylamino) quinolin-3-carbonitrile;
bb) 4- (3-dimethylaminophenylamino) -6-nitroquinolin-3-carbonitrile;
cc) 4- (4-dimethylaminophenylamino) -6-nitroquinolin-3-carbonitrile;
dd) 6-Amino-4- (3-dimethylaminophenylamino) quinoline-3-carbonitrile;
ee) 6-Amino-4- (4-dimethylaminophenylamino) quinoline-3-carbonitrile;
ff) but-2-ynoic acid [4- (3-fluorophenylamino) -3-cyanoquinolin-6-yl] amide;
gg) N- [3-cyano-4- (3-dimethylaminophenylamino) quinolin-6-yl] acrylamide;
hh) N- [3-cyano-4- (4-dimethylaminophenylamino) quinolin-6-yl] acrylamide;
ii) But-2-ynoic acid [3-cyano-4- (3-dimethylaminophenylamino) quinolin-6-yl] amide;
jj) but-2-ynoic acid [3-cyano-4- (4-dimethylaminophenylamino) quinolin-6-yl] amide;
kk) 4- (3-bromophenylamino) -6-dimethylaminoquinoline-3-carbonitrile hydrochloride;
ll) 6-Dimethylamino-4- (3-methoxyphenylamino) quinolin-3-carbonitrile hydrochloride;
mm) 2-Bromo-n- [4- (3-bromophenylamino) -3-cyanoquinolin-6-yl] acetamide;
nn) 6-Iodo-4- (3-methoxyphenylamino) quinolin-3-carbonitrile;
oo) 4- (4-Hydroxy-2-methyl-phenylamino) -6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinoline-3-carbonitrile;
pp) 4- (3-Bromo-phenylamino) -6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinoline-3-carbonitrile;
qq) 6-Methoxy-4- (2- methylsulfanyl-phenylamino) -7- (3-morpholin-4- yl- propoxy) -quinoline-
rr) 4- (4-Hydroxy-3,5-dimethyl-phenylamino) -6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinoline-3-carbonitrile; Or a pharmaceutically acceptable salt thereof.

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同族专利:

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公开号 | 公开日

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WO2001068186A2|2001-09-20|

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NZ521117A|2005-02-25|

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KR20080009294A|2008-01-28|

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TWI262805B|2006-10-01|

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HK1048775A1|2006-01-20|

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EA200200976A1|2003-02-27|

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AT308364T|2005-11-15|

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ES2248302T3|2006-03-16|

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IL151249A|2008-06-05|

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DE60114580T2|2006-07-27|

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CA2402742A1|2001-09-20|

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CN1190197C|2005-02-23|

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JP2003526686A|2003-09-09|

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HK1048775B|2006-01-20|

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NO20024356D0|2002-09-12|

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MXPA02008836A|2003-02-10|

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EP1263503A2|2002-12-11|

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IL151249D0|2003-04-10|

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DE60114580D1|2005-12-08|

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DK1263503T3|2006-02-13|

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BR0109165A|2003-04-22|

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CA2402742C|2009-05-12|

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PL202873B1|2009-07-31|

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PL363072A1|2004-11-15|

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CN1429126A|2003-07-09|

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NO20024356L|2002-11-12|

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WO2001068186A3|2002-01-17|

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ZA200208178B|2004-02-11|

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AU4545201A|2001-09-24|

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KR100817423B1|2008-03-27|

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HU0300547A2|2003-07-28|

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EP1263503B1|2005-11-02|

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AR035482A1|2004-06-02|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-03-13|Priority to US52419600A

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2000-03-13|Priority to US09/524,196

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2001-03-06|Application filed by 아메리칸사이아나미드컴파니

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2002-12-12|Publication of KR20020092987A

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2008-03-27|Application granted

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2008-03-27|Publication of KR100817423B1

优先权:

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申请号 | 申请日 | 专利标题

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US52419600A| true| 2000-03-13|2000-03-13|

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US09/524,196|2000-03-13|