JP2003500397A - 2-NH-pyridones and pyrimidones as MRS inhibitors - Google Patents

Abstract

(57) [Summary] Formula (I) Wherein W is CH, R ¹ is a residue of a 5- or 6-membered heteroaryl ring, or W is N, and R ¹ is a 5- or 6-membered heteroaryl ring or A residue of an aryl ring wherein the heteroaryl or aryl ring is halo, cyano, hydroxy, C _(1-6) alkyl (halo, hydroxy, amino, mono or perfluoro C _(1-3) alkyl, carboxy or C _(1-6) may be substituted by alkoxycarbonyl) C _(3-7) cycloalkyl, C _{(1 -6)} alkoxy, amino, mono- - or di -C _(1-6) alkylamino, acylamino, carboxy, C _(1-6) alkoxycarbonyl, carboxy C _{(1 -6)} alkyloxy, C _(1-6) alkylthio, C _(1-6) alkylsulphinyl, C _(1-6) Al 1 to 3 selected from killsulfonyl, sulfamoyl, mono- and di-C _{( 1-6)} alkylsulfamoyl, carbamoyl, mono- and di-C _(1-6) alkylcarbamoyl, and heterocyclyl R ² is an optionally substituted aryl or an optionally substituted heteroaryl ring; X is CH ₂ or CHR ³ , wherein R ³ is C _(1-6) alkyl, or R ³ is bonded to the ortho position of the aryl or heteroaryl ring of R ² and may contain oxygen or nitrogen as a ring atom. May form a 7-membered ring); Y is C _(1-3) alkylene or C _(4-6) cycloalkylene], and a pyrimidone ring (when W is N) Includes sexual body The compounds, and salts thereof, preferably pharmaceutically acceptable salts, are inhibitors of the bacterial enzyme Staphylococcus aureus methionyl t-RNA synthetase (MRS) and are useful for treating bacterial infections .

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to novel 2-NH-pyridones and pyrimidines, which are inhibitors of methionyl t-RNA synthetase (MRS), methods for producing them, and therapeutic use thereof as antibacterial agents.

BACKGROUND ART t-RNA synthetase is involved in protein biosynthesis, and its inhibition is
Expected to cause cell growth arrest. Thus, for example, the compound mupirocin, which is produced by the organism Pseudomonas fluorescens, is an antibacterial agent and is known as SmithKline Beecham.
used as the active ingredient in the product Bactroban sold by Cham). Mupirocin has proven to be an inhibitor of isoleucyl t-RNA synthetase. Each t-RNA synthetase is an individual drug target.
T-RNA synthetase inhibitors, which are selective for bacterial cells over mammalian cells, are of considerable therapeutic importance as they have potential for use as antibacterial agents.

Recently, Staphylococcus aureus (which aids in methods of identifying inhibitors
The sequence of the t-RNA synthetase gene in organisms such as S. aureus) has been determined. For example, European Patent Application No. 97300317.1 (SmithKline Beecham,
See Staphylococcus aureus MRS).

WO 99 / and WO 00/21949 (SmithKline Beecham, published after the priority date of the present application) disclose 2- (NH or O-), a class of potent inhibitors of methionyl t-RNA synthetase. Substituted) quinolones are disclosed.

DISCLOSURE OF THE INVENTION The present inventors have now discovered a further group of compounds that are potent inhibitors of methionyl t-RNA synthetase, namely 2-NH-substituted (hetero) aryl-fused pyridines and pyrimidones. . Therefore, the present invention provides the formula (I)

[Chemical 7] [Wherein W is CH and R ¹ is a residue of a 5- or 6-membered heteroaryl ring,
Alternatively, W is N and R ¹ is the residue of a 5- or 6-membered heteroaryl ring or aryl ring, wherein heteroaryl or aryl ring is halo, cyano, hydroxy, C _{(1-6 )} Alkyl (optionally substituted by halo, hydroxy, amino, mono or perfluoro C _(1-3) alkyl, carboxy or C _(1-6) alkoxycarbonyl) C _(3-7) cycloalkyl, C _{(1 -6)} Alkoxy, amino, mono- or di-C _(1-6) alkylamino, acylamino, carboxy, C _(1-6) alkoxycarbonyl, carboxy C _(1-6) alkyloxy, C _{(1-6) Alkylthio} , C _(1-6) alkylsulfinyl, C _{(
1-6) selected from} alkylsulfonyl, sulfamoyl, mono- and di-C _(1-6) alkylsulfamoyl, carbamoyl, mono- and di-C _(1-6) alkylcarbamoyl, and heterocyclyl. ~ Is optionally substituted with 3 substituents); R ² is an optionally substituted aryl or an optionally substituted heteroaryl ring; X is CH ₂ or CHR ³ ( Here, R ³ is C _(1
-6) Alkyl, or R ³ may be attached to the ortho position of the aryl or heteroaryl ring of R ² and contain oxygen or nitrogen as ring atoms 5
~ May form a 7-membered ring); Y is C _(1-3) alkylene or C _(4-6) cycloalkylene], and the pyrimidone ring (when W is N) There are provided compounds, including variants, and salts thereof, preferably pharmaceutically acceptable salts.

The compound represented by the formula (I) is Staphylococcus aureus methionyl t
It is an inhibitor of RNA synthetase.

Representative examples where R ¹ is the residue of a heteroaryl ring include rings where the heteroatom is sulfur, eg thieno, or rings where the nitrogen is nitrogen, eg pyrido, pyrimidino and pyrazolo. To be A typical example of the case where R ¹ is the residue of the aryl ring is phenyl. Representative of those substituents include halogen, such as chloro or bromo.

[0008]   formula:

[Chemical 8] As a representative example of the group represented by, 1H-quinazolin-4- ^one in which W is N and R ¹ is the residue of the aryl ring; W is CH and R ¹ is the rest of the heteroaryl ring. The group 7H-thieno [2,3-
b] Pyridin-4-one, 4H-thieno [3,2-b] pyridin-7-one, 4H-
Thieno [3,4-b] pyridin-7-one, 1H-1,8-naphthyridin-4-one; 1H-thieno [3,2-, wherein W is N and R ¹ is a heteroaryl residue. d]
Pyrimidin-4-one, 1H-thieno [2,3-d] pyrimidin-4-one, 1H
-Thieno [3,4-d] pyrimidin-4-one, 1H-pyrido [3,2-d] pyrimidin-4-one, 1H-pyrimido [4,5-d] pyrimidin-4-one, Ohio 1,
7-dihydropyrazolo [3,4-d] pyrimidin-4-one.

Preferably R ¹ forms the residue of the thieno ring.

[0010]   R^TwoRepresentative examples where A is aryl include phenyl and naphthyl
, Each of which may be substituted with up to 4 substituents. Take
A typical example of the substituent is C_(1-6)Alkyl, C_(1-6)Alkoxy, C _(1-6) Alkylthio, heterocyclyl C_(1-6)Alkoxy, halo, cyano
, Amino, sulfamoyl, phenylcarbonyl, aryl and benzyloxy
There is Shi. Preferably, the phenyl or naphthyl is chloro, bromo,
Iodo, methyl, methoxy, allyloxy, phenethyloxy, morpholinopro
Positioned by two or three lipophilic substituents such as poxy or trifluoromethyl
Have been replaced.

Representative examples where R2 is heteroaryl include pyrrolyl, thienyl, furanyl, pyridyl, quinolinyl, benzofuranyl and indolyl, each of which is substituted with up to 3 substituents. May be. Preferably,
The heteroaryl ring is substituted with 2 or 3 lipophilic substituents such as chloro, bromo, iodo, methyl, methoxy, or trifluoromethyl.

Preferred examples of aryl and heteroaryl groups for R ² include phenyl, thienyl and indolyl.

Representative examples of X include CH ₂ or optionally contain oxygen or nitrogen fused with R ² to an aryl or heteroaryl ring 5
To form a 7-membered ring.

Representative examples of R ² X include benzyl, chroman-4-yl, 1,2,3,4
-Tetrahydroquinolin-4-yl, indol-2-ylmethyl, indol-7-ylmethyl, and thien-2-ylmethyl, where the aryl / heteroaryl ring is optionally substituted.

Representative examples of Y include a C ₂ alkylene chain or a 1,2-cyclopentylene group.

Within the scope of the compounds of formula (I) is a first set of pyridone compounds wherein W is CH:

[Chemical 9] And a second set of pyrimidone compounds wherein W is N:

[Chemical 10] Wherein R ¹ , R ² , X and Y are as defined above.

Salts may be formed with inorganic and organic acids. Representative examples of suitable inorganic and organic acids capable of forming pharmaceutically acceptable salts of the compounds of formula (I) are maleic acid, fumaric acid, benzoic acid, ascorbic acid, pamoic acid. , Succinic acid, bismethylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid Acids, glutamic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, cyclohexylsulfamic acid, phosphoric acid and nitric acid.

As used herein, the term “alkyl” and similar terms such as “alkoxy” include all straight chain and branched isomers. As typical examples thereof, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec
-Butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.

Preferred substituents for an alkyl group, unless defined otherwise, are, for example, halogen, cyano, azido, nitro, carboxy, (C _1-6 ) alkoxycarbonyl, carbamoyl, mono-di- (C _{1- 6} ) Alkylcarbamoyl, sulfo, sulfamoyl, mono- or di- (C _1-6 ) alkylsulfamoyl, amino, monopho or di- (C _1-6 ) alkylamino, acylamino, ureido, (
C _1-6 ) alkoxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, aryl, heterocyclyl, hydroxy, (C _1-6 ) alkoxy, acyloxy, oxo, acyl, 2-thienoyl, (C _{1- 6} ) alkylthio,
(C _1-6 ) alkylsulfinyl, (C _1-6 ) alkylsulfonyl, hydroxyimino, (C _1-6 ) alkoxyimino, hydrazino, hydrazono, benzohydroxyimoyl, guanidino, amidino and iminoalkylamino are mentioned.

As used herein, the term “aryl”, unless defined otherwise, is 5
Up to and preferably phenyl or naphthyl optionally substituted with up to 3 substituents.

[0021]   When substituted, the aryl group can have up to 3 substituents.
. Preferred substituents for an aryl group include, for example, unless otherwise defined.
, Halogen, cyano, (C_1-6) Alkyl, monopho or perfluoro (C_1-
Three) Alkyl, (C_3-7) Cycloalkyl, (C_2-6) Alkenyl, (C_1-6)
Alkoxy, (C_2-6) Alkenoxy, aryl (C_1-6) Alkoxy, halo (
C_1-6) Alkyl, hydroxy, amino, mono- or di- (C_1-6) Archi
Luamino, acylamino, nitro, carboxy, (C_1-6) Alkoxycarboni
Le, (C_1-6) Alkenyloxycarbonyl, (C_1-6) Alkoxycarbonyl
(C_1-6) Alkyl, carboxy (C_1-6) Alkyl, (C_1-6) Alkylcal
Bonyloxy, carboxy (C_1-6) Alkyloxy, (C_1-6) Alkoxyca
Lubonyl (C_1-6) Alkoxy, (C_1-6) Alkylthio, (C_1-6) Alkyl
Sulfinyl, (C_1-6) Alkylsulfonyl, sulfamoyl, mono- and
Di- (C_1-6) Alkylsulfamoyl, carbamoyl, mono- and di- (C
_1-6) Alkylcarbamoyl and heterocyclyl.

As used herein, the term “heteroaryl” contains up to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring and substituted with up to 3 substituents. Includes optionally substituted monocycles or fused rings. Preferably, the heteroaryl ring contains 4 to 7, preferably 5 to 6 ring atoms. A fused heteroaryl ring system can include carbocycles and need only include one heterocycle.

As used herein, the term “heterocyclyl” includes up to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring and up to 3 substituents. Includes optionally substituted aromatic and non-aromatic monocycles or fused rings.
Suitably, the heterocycle contains 4 to 7, preferably 5 to 6 ring atoms. A fused heterocyclic ring system can include carbocycles and need only include one heterocycle.

If substituted, the heteroaryl or heterocyclyl group can have up to 3 substituents. Preferred such substituents include those mentioned above for aryl groups and oxo.

As used herein, the terms "halogen" and "halo" include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo and iodo, respectively.

The compounds of the invention are suitably substantially pure, eg at least 50 pure.
%, Suitably at least 60% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at least 95% pure, especially at least 98% pure. Here all percentages are calculated as weight / weight). Impure or less pure forms of the compounds of the invention can be used, for example, in the preparation of purer forms of the same or related compounds (eg, the corresponding derivatives) suitable for pharmaceutical use.

Preferred compounds of formula (I) include 2- [3- (3-bromo-5-methoxy-1H-indol-7-ylmethylamino) prop-1-ylmino] -1H-quinazoline- 4-one; 2- [3- (3-bromo-5-methoxy-1H-indol-7-ylthymeramino) prop-1-ylamino] -1H-thieno [3,2-d] pyrimidin-4-one 2- [3- (3-chloro-5-methoxy-1H-indol-7-ylmethylamino) prop-1-ylamino] -1H-quinazolin-4-one; 2- [3- (3-chloro- 5-Methoxy-1H-indol-7-ylmethylamino) prop-1-ylamino] -1H-thieno [3,2-d] pyrimidin-4-one; 2- [3- (3-chloro-5-methyl -1H-indol-7-ylmethylamino) Propa-1-ylamino] -1H-thieno [3,2-d] pyrimidin-4-one; 2- [3- (6-chloro-8-iodocroman-4-ylamino) prop-1-
Ilamino] -1H-thieno [3,2-d] pyrimidin-4-one; 2- [3- (6,8-dibromochroman-4-ylamino) prop-1-ylamino] -1H-thieno [3,2 -D] pyrimidin-4-one; 2- [3- (6-bromo-8-chloro-1,2,3,4-tetrahydroquinoline-
4-ylamino) prop-1-ylamino] -1H-quinazolin-4-one; 2- [3- (6,8-dibromo-1,2,3,4-tetrahumancelloquinolin-4-ylamino) proper 1-ylamino] -1H-thieno [3,2-d] pyrimidine-4
2- [3- (6,8-dibromo-1,2,3,4-tetrahydroquinolin-4-ylamino) prop-1-ylamino] -1H-quinazolin-4-one; 2- [3- (4,6-Dichloro-1H-indol-2-ylmethylamino) prop-1-ylamino] -1H-quinazolin-4-one; 2- [3- (4,6-dichloro-1H-indole-2- Ilmethylamino) prop-1-ylamino] -1H-thieno [3,2-d] pyrimidin-4-one; 2- {3- [3,5-dibromo-2- (3-morpholinopropoxy) benzylamino] -Prop-1-ylamino} -1H-quinazolin-4-one; 2- {3- [4,6-dichloro-1- (2-hydroxyethyl) -1H-indol-2-ylmethylamino] prop-1 -Ilamino} -1H-thieno [3,2-d
] Pyrimidin-4-one; and 2- [3- (2-ethoxy-5-iodo-3-methylbenzylamino) proper
1-ylamino] -1H-quinazolin-4-one.

[0028]   The compound represented by the formula (I) has the formula (II):

[Chemical 11] [Wherein R ¹ , W and Y are the same as defined above], and (a) a compound of the formula (I) wherein X is CH ₂ under the conditions of reductive alkylation (III): R ² CHO (III) [wherein R ² is the same as defined above], and (b) CH _{2 in} which X is substituted by C _(1-6) alkyl Or a compound of formula (I) wherein R ² and X are linked by a 5 to 7 membered ring which may contain oxygen or nitrogen, under the conditions of reductive alkylation, formula (IV)
R ² R ³ CO (IV) [wherein R ² and R ³ are the same as defined above] and can be prepared by reacting any of the ketones.

Suitable reductive alkylation conditions are well known in the art, eg sodium triacetoxyborohydride in a solvent system such as DMF / acetic acid or sodium cyanoborohydride in methanol / acetic acid. Is used.
Reductive alkylation with aldehydes is typically carried out at room temperature for 1-16 hours. Reductive alkylation with ketones is typically 16-4 in refluxing methanol.
It will be held for 0 hours.

[0030]   The compound represented by the formula (IB) has the formula (V):

[Chemical 12] [Wherein R ¹ is the same as defined above, and R ⁴ is a leaving group such as halo, for example, chloro, or C _(1-6) alkylthio]. ): R ² XNHYCH ₂ NH ₂ (VI), wherein R ² , X and Y are the same as defined above, and can be prepared by reacting with an amine or an active derivative thereof.

Suitable conditions are well known in the art and include the use of a large excess of the compound of formula (VI) to complete the reaction and heating at a temperature of 60 to 130 ° C. . It may be advantageous to add a base, for example a tertiary base such as N, N-di (cyclohexyl) ethylamine.

[0032]   The compound represented by the formula (A) has the formula (VII):

[Chemical 13] [Wherein R ¹ is the same as defined above, R ⁵ is a leaving group such as halo, for example chloro, and R ⁶ is C _(1-6) alkyl, such as methyl or ethyl, Or an aryl C _(1-4) alkyl group] is reacted with an amine of formula (VI) or an active derivative thereof as defined above to form an intermediate, followed by acidic hydrolysis. According to formula (IA)
It can also be prepared by converting to the compound shown by.

Suitable conditions are well known in the art and include the use of a large excess of the compound of formula (VI) to complete the reaction and heating at a temperature of 60-130 ° C. . It may be advantageous to add a base, for example a tertiary base such as N, N-di (cyclohexyl) ethylamine. Acidic hydrolysis can be carried out with refluxing concentrated hydrochloric acid when R ⁶ is methyl and with trifluoroacetic acid at room temperature when R ⁶ is 4-methoxybenzyl.

A compound of formula (II) can be prepared by reacting a compound of formula (VII) with a compound of formula (VI) wherein R ² is hydrogen.

The compounds of the present invention may be used in Haemophilus, for example Haemophilus
H. influenzae Q1; Moraxella, eg, M. catarrhalis 1502; Streptococcus (St.
reptococci), for example, S. pyogenes CN
10 and S. pneumoniae R6; Staphylococci, for example Staphylococcus aureus Oxford; Escherichia, for example E. coli. DC0 and Enterococci
, Is active against both Gram-negative and Gram-positive organisms, including, for example, Enterococcus faecalis I. In addition, the compounds of the present invention may be used in combination with other antibacterial agents such as β-lactam antibiotics such as methicillin;
Macrolides; Staphylococcus organisms such as Staphylococcus aureus and Staphylococcus epidermidis resistant to aminoglycosides and lincosamides, including multidrug resistance. It is active against coagulase-negative strains of the genus Phylococcus. Therefore,
The compounds of the present invention are useful in the treatment of MRSA, MRCNS and MRSE.
The compounds of the present invention also include Enterococcus vulgaris strains, including vancomycin resistant strains.
It is active against S. faecalis strains and is therefore useful in treating infections associated with VRE organisms. Furthermore, the compounds of the present invention are useful in the treatment of Staphylococcus organisms that are resistant to mupirocin.

Bacterial infections that may be treated include respiratory tract infections in humans, otitis, meningitis, endocarditis, skin and soft tissue infections, mastitis in cattle, and infections in animals such as pigs and cattle. To be Accordingly, in a further aspect, the present invention is a method of treating a bacterial infection in a human or non-human animal, wherein the therapeutically effective amount of the compound of formula (I) is provided to a human or non-human animal in need of such treatment. Methods are provided that include administering a compound.

The present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier or excipient.

The present invention also relates to a method of treating bacterial infections in animals, in particular humans and domesticated mammals, wherein the compound of formula (I) or the invention is used in patients in need of such treatment. A method comprising administering the composition of claim 1.

The invention further provides the use of a compound of formula (I) in the preparation of a pharmaceutical composition for the treatment of bacterial infections.

The compounds and compositions of this invention may be formulated for administration in any convenient way for use in human or veterinary medicine, due to their analogy with other antibiotics.

The compounds and compositions of the invention may be formulated for administration by any route, for example the oral, topical or parenteral routes. The composition is, for example, a tablet, a capsule, a powder, a granule, a lozenge, a cream, a syrup, or a liquid preparation which can be formulated in a sterile dosage form for oral administration or parenteral administration by injection or infusion, For example, it can be prepared in the form of solution or suspension.

Tablets and capsules for oral administration may be in unit dosage form, eg
Binders such as syrup, gum arabic, gelatin, sorbitan, tragacanth, or polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitan or glycine; tableting lubricants,
For example, magnesium stearate, talc, polyethylene glycol or silica; disintegrants such as potato starch; and pharmaceutically acceptable wetting agents,
It may contain conventional excipients including, for example, sodium lauryl sulfate. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid formulations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or dried for reconstitution with water or other suitable vehicle before use. It can be offered as a product. Such liquid formulations include, for example, suspending agents such as sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifiers such as lecithin, sorbitan monooleate or Gum arabic; non-aqueous vehicles (including edible oils) such as tonsil oil, oily esters (eg glycerin), propylene glycol, or ethyl alcohol; preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid. And optionally containing conventional additives including conventional flavoring agents and colorants.

Compositions of the invention intended for topical administration are, for example, in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, impregnated dressings, and aerosols. Well, it may contain suitable conventional additives, including, for example, preservatives, drug penetration aids, and humectants in ointments and creams. Such topical formulations may contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may make up from about 1% to about 98% by weight of the formulation, and more usually,
They make up up to about 80% by weight of the formulation.

The compositions of the present invention may be formulated as conventional suppository bases, eg suppositories which may also contain cocoa butter or other glycerides.

Compositions of the invention intended for parenteral administration may conveniently be in fluid unit dosage form prepared using the compound of interest and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. In preparing a liquid preparation, the compound is dissolved in an injectable solution, sterilized by filtration, filled in a suitable vial or ampoule, and then sealed. Advantageously, conventional additives, including, for example, local anesthetics, preservatives, and buffers, can be dissolved in the vehicle. To enhance the stability of the solution, the composition is frozen in a vial after filling, then the water is removed under vacuum; the resulting lyophilized powder is then sealed in the vial and used The liquid can be reconstituted by supplying the previously supplied vial for injection. Parenteral suspensions can be prepared in substantially the same manner except that the compound is suspended in the vehicle rather than dissolved and sterilization cannot be accomplished by filtration. The compound can alternatively be sterilized by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in such suspensions to facilitate uniform distribution of the compound.

The compound or composition of the invention is suitably administered to the patient in an antibacterial effective amount.

Compositions of the invention suitably contain 0.1% of a compound of the invention, depending on the method of administration.
%, Preferably 60% by weight (based on the total weight of the composition).

The compound of the invention is suitably administered to a patient at a daily dose of 1.0 to 50 mg / kg body weight. For a human adult (body weight about 70 kg), 50-300 mg of a compound of the invention, eg, about 1500 mg, can be administered daily. Suitably, the adult human dose is 5-20 mg / kg per day. However,
Higher or lower doses can be used according to normal clinical practice.

When the composition of the invention is provided in unit dosage form, each unit dose may suitably comprise 25-1000 mg, preferably 50-500 mg of a compound of the invention.

[0051]   The following example illustrates the invention.

General Reductive Amination Method: Amine (0.2 mmol) in methanol (2 ml
) Suspension in sodium acetate (if the amine is present as the dihydrochloride salt, 0.5%
containing mmol), methanol (2 ml) and acetic acid (0.033 ml).
Aldecht in (0.2 mmol) was added. After stirring for 10 minutes under argon, NaCNBH ₃ (24 mg, 0.4 mmol) in MeOH (1 ml) was added and the reaction was stirred for 16 hours. The reaction mixture was loaded onto a 2 g Varian Bomd Elute SCX cartridge flushed with MeOH (8 ml). Then the cartridge was eluted with 0.2 M NH ₃ 8 ml in MeOH, and evaporated to dryness The eluate. The residue, 2-10% in _{CH 2 Cl 2 (9: 1} M
It was purified by silica gel chromatography eluting with eOH / 20M NH _3). Product containing fractions were combined and evaporated under reduced pressure to give the product as a white solid. The solid was dissolved in 1.0 M HCl in methanol (0.4 ml) and the solution was evaporated to dryness to convert it to the corresponding dihydrochloride salt. Another method using polymer-supported cyanoborohydride was also used. Instead of sodium cyanoborohydride, (polystyrylmethyl) trimethylammonium cyanoborohydride (Novobiochem) (3.64 mmol /
g, 100 mg) was used. The reaction was worked up by filtration, evaporation and then silica gel chromatography as described above.

General method for alkylation of phenol: To a solution of phenol (1.2 mmol) and ethyl iodide (480 ul, 6 mmol) in dimethylformamide (2 ml) was added potassium carbonate (330 mg, 2.4 mmol). 6 under argon
After stirring for 16 hours at 5 ° C., the suspension was diluted with diethyl ether, washed with water,
Dried (MgSO _4), was evaporated to get the product.

Intermediate 1-N- (3-aminoprop-1-yl) -3,4-dichlorobenzylamine-3,4 in 1,3-diaminopropane (42 ml) in dry THF (200 ml) at 60 ° C. -Dichlorobenzyl chloride (13.9 ml, 100 mm
ol) in 90 ml dry THF was added dropwise over 3 hours. The mixture was held at 60 ° C for an additional 15 minutes, then at 25 ° C for 3 days. The precipitate was removed by filtration and the mother liquor was concentrated in vacuo. The residue was partitioned between water and t-butyl methyl ether (TBME). Aqueous HCl solution (2M) was added to the organic layer and the mixture was filtered. The layers were separated and NaOH was added to the aqueous layer with stirring. The resulting mixture was extracted with TBME, the organic extracts were dried (Na ₂ CO ₃ ), filtered and the solvent was evaporated to give the title compound as a slightly cloudy oil (18.2g.
, 78%). δ _H (CDCl ₃ ) 1.20 (br, s, ca. 3H), 1.58-
1.71 (m, 2H), 2.67 (t, J = 6.9, 2H), 2.78 (t, J = 6)
.8, 2H), 3.74 (s, 2H), 7.15 (dd, J = 8.2, 2.0, 1)
, 7.37 (d, J = 8.2, 1H), 7.43 (d, J = 1.9, 1H); MS (
ES ⁺ ) 233 (MH ⁺ , 13%), 159 (100).

[0055]   Intermediate 2: 2- (3-Amolypropylamino) -1H-quinazolin-4-one   2- (Methylsulfanyl) -1H-quinazolin-4-one (20 g; Chern et
 al., Tetrahedron Asymm. 1996, 7, 1641-1648) and 1,3-diaminopropa
(104 ml) was heated to 140 ° C. in a sealed vessel for 48 hours. Yellow color after cooling
The crystalline solid was filtered off. The remaining reaction mixture was concentrated in vacuo and triturated with methanol.
And purified by column chromatography. Crystal and chromatography
Combined with the material obtained by- to give the title compound: (12 g, 53%). δ _H (D₆-DMSO) 1.63 (m, 2H), 2.64 (m, 2H), 3.39 (
m, 2H), 5.10 (v. br., 3H), 6.87 (b, ca. 1H), 7.
06 (m, 1H), 7.21 (m, 1H), 7.52 (m, 1H), 7.87 (m
, 1H).

Intermediate 3: 2- (3-Aminopropylamino) -1H0 thieno [3,2-d] pyrimidin-4-one a) 1H-thieno [3,2-d] pyrimidin-4-one-2 Potassium thiolate In a solution of KOH (25 g) in ethanol (1 liter) 3- (3-benzoylthioureido) -2-thiophenecarboxylic acid methyl ester (75 g; Gutschow,
J. Het. Chem. 1996, 33, 355-360) was added and the mixture was heated under reflux for 2.5 hours. The lemon-colored solid was filtered off to give the title compound with a purity of about 85% combined with the benzoate impurity, which was used in the next step without further purification: (46 g). δ _H (d ₆ -D
MSO) 6.87 (m, 1H), 7.22 (m, 1H), 10.35 (br, 1H)
).

B) 2-Methylsulfanyl-1H-thieno [3,2-d] pyrimidin-4-one 1H-thieno [3,2-d] pyrimidine-4 having a purity of about 85% in water (1 liter).
-On-2-potassium thiolate (46 g) was added. Methyl iodide (13m
1) was added and the mixture was stirred for 3 hours. The white precipitate was filtered and dried to give the title compound as an off-white solid: 30g, 82%). δ _H (d ₆ −
DMSO) 2.55 (s, 3H), 7.31 (d, J = 5.2Hz, 1H), 8.1
3 (d.J = 5.2 Hz, 1H), 12.78 (br, 1H).

C) 2- (3-Aminopropylamino) -1H-thieno-anefphosimpyrimidin-4-one In a similar manner as described for Intermediate 2, 2-methylsulfanyl 01H-thieno [3,2- Treatment of d] pyrimidin-4-one (20 g) gave the title compound: (8.0 g, 35%). δH- (d6-DMSO) 1.96 (m, 2H), 2.
96 (m, 2H), 3.69 (m, 2H), 5.16 (br, ca. 4H (H ₂ O
(Below the peak)), 7.54 (d, J = 5,1H), 8.28 (d, J = 5,1H)
.

If the dihydrochloride salts of intermediates 2 or 3 were used, they were obtained quantitatively from the free amines by treatment with concentrated aqueous HCl solution in methanol and then evaporation.

Example 1-6- [3- (3,5-Dibromobenzylamino) prop-1-ylamino] -7H-thieno [2,3-b] pyridin-4-one dihydrochloride a) N -(3,5-Dibromobenzyl) propane-1,3-diamine THF (70 ml) with 3,5-dibromobenzyl bromide (9.96 g, 30.
2 mmol) was dissolved and propane-1,3-diamine (12.6 ml, 151 mm
ol) in THF (50 ml) at 60 ° C. over 90 minutes. The solution was stirred under argon for a further 30 minutes, filtered and the filtrate was concentrated. The residue was partitioned between tert- butyl methyl ether and H _{2 O,} the organic layer was separated,
Aqueous HCl (1M) was added. The aqueous layer was separated, filtered and basified to pH 13 (NaOH pellets). The solution was extracted with CHCl ₃ , dried (K ₂ CO ₃ ) and evaporated under reduced pressure to give the title compound as a yellow oil (6.21 g, 19).
mmol): δ _H (CDCl ₃ ) 1.36 (br, s, 3H + H ₂ O), 1.6
5 (m, 2H), 2.67 (t, J6.7, 2H), 2.79 (t, J6.7, 2H)
), 3.74 (s, 2H), 7.42 (d, J1.6, 2H), 7.54 (t, J1)
.6, 1H); MS (ES +) 323 (100%, [M + H] ⁺ ), 306 (75
), 249 (100).

B) 6- [3- (3,5-dibromobenzylamino) prop-1-ylamino]-
4-Methoxythieno [2,3-b] pyridine 2-chloro-4-methoxythieno [2,3-b] pyridine (J. Chem. Res. Minip
rint 1985, 2501; 275 mg, 1.38 mmol) in a Wheaton reactor vial at 130 ° C. for 40 minutes, N- (3,5-dibromobenzyl) propane-1,3-diamine (1.33 g) of Example 1a. , 4.14 mmol). The resulting oil was purified by flash chromatography on silica gel, eluting with 5-10% [10: 1 MeOH / conc NH ₃ (aq)] in CH ₂ Cl ₂ to give a white. The title compound was obtained as a solid (70 mg, 0.1
44 mmol); δ _H (CD ₃ OD) 1.83 (m, 2H), 2.66 (t, J7)
.0, 2H), 3.44 (t, J6.7, 2H), 3.69 (s, 2H), 3.91
(S, 3H), 5.98 (s, 1H), 6.94 (d, J5.9, 1H), 7.11
(D, J5.9, 1H), 7.48 (d, J1.7, 2H), 7.58 (t, J1.
7,1H); MS (ES +) 486 (50%, [M + H] ⁺ ), 186 (100).
.

C) 6- [3- (3,5-dibromobenzylamino) prop-1-ylamino]-
7H-thieno [2,3-b] pyridin-4-one dihydrochloride 1,4-dioxane 82 ml) The compound of Example 1b (70 mg, 0.144).
Concentrated hydrochloric acid (8 ml) was added to (mmol). The mixture was refluxed at 110 ° C. for 32 hours. The mixture was filtered and evaporated under reduced pressure to a low volume to give an off-white residue which was chromatographed on silica gel 5-10-25% [1
Purification by eluting with 0: 1 MeOH / conc. NH ₃ (aq)]. The isolated material was dissolved in MeOH and concentrated hydrochloric acid was added. Excess solvent was evaporated under reduced pressure to give the title compound as a white solid, isolated as the dihydrochloride salt (5 mg, 0.00
9 mmol); δ _H (CD ₃ OD) 1.78 (m, 2H), 2.70 (t, J7.
0,2H), 3.30 (t, J6.6,2H ), 3.76 (s, 2H, ArCH 2 N
), 5.39 (s, 1H, HCCO), 6.85 (d, 1H, J5.7, thiophene), 7.09 (d, 1H, J5.7, thiophene), 7.45 (d, 2H) , J1.
7, BrCCHCCH ₂ ), 7.56 (t, 1H, J1.7, brCCHCBr);
MS (ES ⁺ ) 472 (100%).

Example 2-5- [3- (3,4-dichlorobenzylamino) prop-1-ylamino] -4H-thieno [3,2-b] pyridin-7-one dihydrochloride a) 5 1-To a solution of -chloro-7-methoxythieno [3,2-b] pyridine NaOMe (400 mg, 7.35 mmol) in THF (10 ml).
5-Crown-5 (1.46 ml, 7.35 mmol) was added and stirred for 15 minutes. 5,7-Dichlorothieno [3,2-b] pyridine (J. Chem. Res. Miniprint 19
80, 0113; 1 g, 4.9 mmol) was added to give a deep purple suspension which was stirred under argon for 90 minutes. The reaction mixture was treated with NH ₄ Cl (aq) and tert-
Partition with butyl methyl ether, separate layers, wash organic layer with brine,
Concentrated under reduced pressure. The residue was flash chromatographed on silica gel, eluting with 4: 1-3: 1 [hexane / ethyl acetate] to give the title compound as an off-white solid (790mg, 3.96mmol); _H (CDCl ₃ )
4.05 (s, 3H), 6.74 (s, 1H), 7.44 (d, J5.4, 1H),
7.70 (d, J5.4, 1H); MS (ES +) 200 (75%, [M + H] ⁺ ).
164 (100), 149 (63).

[0064]   b) 5- [3- (3,4-dichlorobenzylamino) prop-1-ylamino]-
7-Methoxythieno [3,2-b] pyridine   The 5-chloro-7-methoxythieno [3,2-b] pyridine of Example 2a (4.0 g
) And N- (3-aminoprop-1-yl) -3,4-dichlorobenzylamine (about
0.59 ml) and maintained at 85 ° C for 15 hours, then at 125 ° C for 4 hours.
Maintained for a while. Column chromatography (silica gel, MeOH: NH_Three: CH
_TwoCl_Two 10: 1: 100 → 30: 3: 200) to contain the title compound
5-chloro-7-methoxythieno [3,2-b] pyridine (0.17 g)
Was collected and again subjected to column chromatography (silica gel, MeOH:
NH_Three: CH_TwoCl_Two 10: 1: 100) and labeled as a yellow film.
The above compound (17 mg) was obtained: δ_H(CDCl_Three) 1.71 (br, s, 1H, N
H), 1.78-1.90 (m, 2H, CH_TwoCH_TwoCH_Two), 2.76 (t, J
6.4, 2H, CH_TwoNHCH_Two) 3.47-3.55 (m, 2H, CH_TwoN)
3.74 (s, 2H, ArCH_Two) 3.95 (s, 3H, OCH_Three) 4.97
(Br, s, 1H, NH), 5.83 (s, 1H, CHCO), 7.12-7.1
7 (m, 2H, 2Ar-H), 7.36 (d, J8.2, 1H, Ar-H), 7.4
4 (d, J1.9, 1H, ArH), 7.50 (d, J5.4, 1H, Ar-H);
m / z (ESI) 396 (MH⁺, 20%), 221 (100%).

C) 5- [3- (3,4-dichlorobenzylamino) prop-1-ylamino]-
4H-thieno [3,2-b] pyridin-7-one dihydrochloride Dioxane (1 ml) and the compound of Example 2 (17 mg) in concentrated aqueous HCl (5 ml) were heated at reflux for 48 hours. Evaporate the volatiles in vacuo,
The residue was triturated with CHCl ₃ , filtered and off-white solid to give the title compound (18 mg): δH (CD ₃ OD) 2.08-2.25 (m, 2H).
, CH ₂ CH ₂ CH ₂ ), 3.21 to 3.31 (m, 2H, CH ₂ NHCH ₂ ),
_{3.54-3.63 (m, 2H, CH 2} N), 4.29 (s, 2H, ArCH 2),
6.27 (s, 1H, CHCO), 7.45-7.54 (m, 2H, 2Ar-H),
7.66 (d, J n.d., 1H, Ar-H), 7.80 (d, J n.d., 1H,
Ar-H), 8.10 (d, 1H, Jn.d., ArH); m / z (ESI) 382.
(MH ⁺ , 68%), 207 (100%).

[0066]   Example 3-5- [3- (3,5-diflomobenzylamino) prop-1-yl
Amino] -4H-thieno [3,2-b] pyridin-7-one dihydrochloride   a) 5- [3- (3,5-dibromobenzylamino) prop-1-ylamino]-
7-Methoxythieno [3,2-b] pyridine   The 5-chloro-7-methoxythieno [3,2-b] pyridine of Example 2a (345
mg, 1.73 mmol) of N- (3,5-dibromobenzyl) propa of Example 1a.
With 1,3-diamine (1.67 g, 5.19 mmol)
Heated at 130 ° C. for 40 hours in n. The oil obtained is
Flash chromatography on silica gel, CH_TwoCl_TwoMedium 5-10
% [10: 1 MeOH / dark NH_Three(Aqueous solution)]
The title compound was obtained as a white solid (40 mg, 0.08 mmol); δ_H(CD
_ThreeOD) 1.86 (m, 2H), 2.69 (t, J 7.0, 2H), 3.45 (t
, J 6.8, 2H), 3.72 (s, 2H), 3.96 (s, 3H), 6.06 (
s, 1H), 7.11 (d, J 5.3, 1H), 7.49-7.53 (m, 2H)
, 7.59-7.61 (m, 2H); MS (ES +) 486 (100%, [M + H]. ⁺ ).

B) 5- [3- (3,5-dibromobenzylamino) prop-1-ylamino]-
4H-thieno [3,2-b] pyridin-7-one dihydrochloride The compound of Example 3a (40 mg, 0.08 m in 1, 4-dioxane (2 ml).
Concentrated hydrochloric acid (8 ml) was added to (mol). The mixture was refluxed at 110 ° C. for 32 hours. The mixture was filtered and evaporated under reduced pressure to give an off-white residue which was flash chromatographed on silica gel, 5-CH ₂ in CH ₂ Cl _2.
10-25% was purified by eluting with [10 1 MeOH / conc. NH ₃ (aq). The isolated material was dissolved in MeOH and concentrated hydrochloric acid was added. Evaporation of the solvent under reduced pressure gave the title compound as a white solid, isolated as the dihydrochloride salt (4mg).
, 0.007 mmol); δ _H (CD ₃ OD) 2.18 (m, 2H), 3.28 (
m, 2H), 3.60 (t, J 6.6, 2H), 4.30 (s, 2H, ArCH ₂
N), 6.27 (s, 1H, HCCO), 7.47 (d, J 5.4, 1H, thiophene), 7.77 (d, J 1.4, 2H, HCCCH2), 7.90 ( t, J 1.
4, BrCCHCBr), 8.08d, J 5.4, 1H, thiophene); MS (E
S +) 472 (100%, [M + H] ⁺ ).

Example 4-2- [3- (3,4-Dichlorobenzylamino) prop-1-ylamino] -1H-1,8-naphthyridin-4-one dihydrochloride a) 2-chloro-4 -Methoxy-1,8-naphthyridine 2,4-dichloro-1,8-naphthyridine (Berichte 1927, 60, 407; 0.43
To g) was added NaOMe in MeOH (1M, 4.3 ml) and the mixture was heated at reflux for 30 minutes. EtOAc (about 5 ml) was added, then removed in vacuo and the process repeated. The resulting material was subjected to column chromatography (silica gel, EtOAc: hexane 2: 1 → 3: 1 → EtOAc) to give 4-chloro-2-methoxy-1,8-naphthyridine (211 mg, colorless crystals). Obtained, and then the title compound (colorless crystals, 117 mg) was obtained. δ (CDCl ₃ ) 4.09
(S, 3H, OCH ₃ ), 6.83 (s, 1H, 3-H), 7.46 (dd, J
8.3, 4.3, 1H, 6-H), 8.50 (dd, Jn.d., 1H), 9.07
(Dd, J n.d., 1H); m / z (ESI) 217 (MNa ⁺ , 5%), 19
5 (MH +, 100%).

[0069]   b) 2- [3- (3,4-dichlorobenzylamino) prop-1-ylamino]-
4-methoxy-1,8-naphthyridine   2-Chloro-4-methoxy-1,8-naphthyridine of Example 4a (0.11 g)
And N- (3-aminoprop-1-yl) -3,4-dichlorobenzylamine (
About 0.17 ml) of acetonitrile (1 ml) and N, N-diisopropylethyl ether
The mixture in luamine (1 ml) was maintained at 85 ° C for 4 hours, then at 25 ° C for 15 hours.
Temperature and then again at 85 ° C. for 24 hours. Evaporate the volatiles under vacuum
Column chromatography of the residue (silica gel, MeOH: NH_Three: CH
_TwoCl_Two 10: 1: 100) to give the title compound as a slightly yellow oil.
Obtained (163 mg): δ (CDCl_Three) 1.79-1.91 (m, 3H, CH_TwoC
H_TwoCH_Two + NH), 2.77 (t, J 6.3, 2H, CH_TwoNHCH_Two),
3.71 (t, J 6.2, 2H, CH_TwoN), 3.74 (s, 2H, ArCH_Two)
5.76 (br, t, J n.d., 1H, NH), 5.89 (s, 1H, CHC
O), 7.07 (dd, J 8.0, 4.5, 1H, Ar-H), 7.14 (dd, J
 n.d., 1H, Ar-H), 7.34 (d, J 8.2, 1H, Ar-H), 7.4
4 (d, J 1.9, 1H, Ar-H), 8.22 (dd, J nd., 1H, ArH
), 8.75 (dd, J n.d., 1H, Ar-H); m / z (ESI) 391 (
MH⁺, 32%), 216 (100%).

C) 2- [3- (3,4-dichlorobenzylamino) prop-1-ylamino]-
1H-1,8-Naphthyridin-4-one dihydrochloride The compound of Example 4b (122 mg) in dioxane (2 ml) and concentrated aqueous HCl (10 ml) was heated at reflux for 20 hours. The volatiles were evaporated under vacuum and the residue was triturated with CHCl ₃ and filtered to give the title compound as a colorless solid (110 mg): δH (CD ₃ OD) 2.08-2.21 (m, 2H
, CH ₂ CH ₂ CH ₂ ), 3.17-3.25 (m, 2H, CH ₂ NHCH ₂ ),
_{3.66-3.72 (m, 2H, CH 2} N), 4.26 (s, 2H, ArCH 2),
6.40 (s, 1H, CHCO), 7.45-7.55 (m, 2H, 2Ar-H),
7.62 (d, J 8.3, 1H, Ar-H), 7.75 (d. J 2.0, 1H, Ar
-H), 8.61-8.83 (m, 2H, 2ArH); m / z (ESI) 377 (
MH +, 28%), 202 (100%).

[0071]   Example 5-2- [3- (3,5-dibromobenzylamino) prop-1-yl
Amino] -1H-quinazolin-4-one   2-Methylthioquinazolin-4-one (Tetrahedron: Asymmetry 1996, 7, 16
41; 100 mg, 0.52 mmol) was added to N- (3,5-dibromoben of Example 1a).
Zil) propane-1,3-diamine (334 mg, 1 mmol), with Who
Heated at 85 ° C. for 24 hours in an aton Lactivial. Silica gel
Flash chromatography on a_TwoCl_TwoMedium 5-10-20%
[10: 1 MeOH / concentrated NH_Three(Aqueous solution)], an off-white solid
The product was obtained as (150 mg, 0.32 mmol); δ_H(CDCl_Three/ CD _Three OD) 1.93 (m, 2H), 2.75 (t, J 6.7, 2H), 3.59 (t
, J 6.5, 2H), 3.81 (s, 2H), 7.31 (m, 2H), 7.57 (
s, 2H), 7.65 (m, 2H), 8.09 (m, 1H); MS (ES +) 46.
7 (100%, [M + H]⁺).

Example 6-2- [3- (3,5-Dibromobenzylamino) prop-1-ylamino] -1H-thieno [3,2-d] pyrimidin-4-one dihydrochloride Example 5a N- (3,5-dibromobenzyl) propane-1,3-diamine (0
.105 g, 0.3 mmol) and 2-ethylsulfanyl-1H-thieno [3,2-
d] pyrimidin-4-one (J. Med. Chem., 1995, 38, 2763; 0.035 g, 0.03 g.
165 mmol) and reacted at 125 ° C. for 24 hours. The mixture was pre-absorbed on silica, then purified by flash chromatography, eluting with 0-10% 10% 0.880 ammonia in methanol in dichloromethane to give an off-white solid. The base was obtained. This was suspended in methanol and treated with hydrochloric acid to give the title compound as an off-white powder (0.
_{023g, 26%); δ H} (CD 3 OD) 2.2-2.35 (2H, m), 3.3
5 (2H, t), 3.77 (2H, t), 4.35 (2H, s), 7.48 (1H
, Br d), 7.85-7.95 (3H, m), and 8.25 (1H, d); L.
C / MS (ES +) 471, 473, 475 (50, 100, 50%, MH ⁺ )
.

Example 7-6- [3- (3,5-Diflomobenzylamino) prop-1-ylamino] -1,7-dihydropyrazolo [3,4-d] pyrimidin-4-one a) 6-Methylsulfanyl-1,7-dihydropyrazolo [3,4-d] pyrimidin-4-one potassium dicarbonate (300 mg, 3.0 mmol) and methyl iodide (0.2 m
4-Hydroxy-6-mercaptopyrazolo [3,4-d] pyrimidine (500 mg, 2.97 mmol) was added to a solution of 1, 3.0 mmol) in EtOH (15 ml) and stirred under argon for 16 hours. The reaction mixture was concentrated under reduced pressure and CH ₂ Cl ₂
: MeOH (10: 1) was dissolved in, filtered, and the filtrate was evaporated under reduced pressure to give the title compound as an off-white solid (300mg, 1.6mmol); δ _H
(CDCl ₃ / CD ₃ OD) 2.45 (s, 3H), 7.85 (s, 1H); MS
(APCI +) 183 (100%, [M + H] ⁺ ); MS (APCI-) 181 (
100%, [M−H] ⁻ ).

B) 6- [3- (3,5-dibromobenzylamino) prop-1-ylamino]-
1,7-Dihydropyrazolo [3,4-d] pyrimidin-4-one The 6-methylsulfanyl-1,7-dihydropyrazolo [3,4-d] of Example 7a.
Pyrimidin-4-one (100 mg, 0.55 mmol) was added to N- (3 of Example 5a.
, 5-Dibromobenzyl) propane-1,3-diamine (350 mg, 1.1 mmo
Heated to 90 ° C. for 24 hours in a Wheaton Lactivial with l). The reaction mixture was subjected to flash chromatography on silica gel, CH
Elution with 10-25-40% [10: 1 MeOH / conc. NH3 (aq)] in 2Cl2 gave the title compound as a white solid (20mg, 0.04mmol);
H (CDCl ₃ / CD ₃ OD) 1.80 (m, 2H), 2.66 (t, J 6.7,
2H), 3.45 (t, J 6.6, 2H), 3.72 (s, 2H), 7.42 (s
, 2H), 7.57 (s, 1H), 7.91 (s, 1H); MS (ES +) 457.
(100%, [M + H] ⁺ ).

Example 8-2- [3- (3-Bromo-5-methoxy-1H-indole-7
-Ylmethylamino) prop-1-ylamino] -1H-quinazolin-4-one a) 5-methoxyindoline-7-carbaldehyde 1- (tert-butoxycarbonyl) -5-methoxyindoline (Heterocycl
es, 1992, 34, 1031; 1.75 g, 7.0 mmol) in dry THF,
It was treated with TMEDA (1.4 ml) and cooled to -78 ° C under an argon atmosphere.
A solution of s-butyllithium (1.3M in cyclohexane, 5.18 ml) was added dropwise. After stirring at −78 ° C. for 1 hour, the solution was dried with DMF (1.08 ml, 14 m).
mol) and stirred for a further 0.5 h. The cooling bath was then removed and the solution was allowed to come to room temperature for 1 hour. The reaction mixture was quenched with 10% aq. NH ₄ Cl and the product was extracted into ethyl acetate. The extracts were combined, washed with water and brine, dried (MgSO _4), and evaporated. The residue was chromatographed on Keiselgel 60, eluting with 0-20% ethyl acetate in hexane. Fractions containing product were combined and evaporated to give the title compound contaminated with 35% by weight of the corresponding N-Boc analog (510 mg); δH (CDCl,
3.03 (2H, t, J = 8.0 Hz, CH ₂ ), 3.76 (2H, t, among others)
, J = 8.1 Hz, CH ₂ NH), 3.77 (3 H, s, OMe), 6.42 (1 H
, Br.s, NH), 6.73 (1H, J = 0.8Hz, Ar-H), 6.90-6.
92 (1H, m, Ar-H), 9.79 (1H, s, CHOO).

B) 5-Methoxyindole-7-carbaldehyde a) product (80 mg; 5-methoxyindoline-7-carbaldehyde 0)
(Containing 0.3 mmol) was dissolved in dichloromethane (10 ml), and MnO ₂ (3
44 mg, 4.0 mmol). The reaction mixture was stirred at room temperature for 16 hours, filtered through Celite and the solvent removed in vacuo. Kieselgel the residue
Chromatography on 60, eluting with 0-20% ethyl acetate in hexanes, gave the title compound as a pale yellow solid (23mg, 44%). δH (CDC
l ₃ ) 3.91 (3H, s, OMe), 6.56 (1H, dd, J = 2.2,3.2H
z, 3-H), 7.28 (1H, d, J = 2.3 Hz, Ar-H), 7.33 (1H
, T, J = 2.6 Hz, 2-H), 7.46 (1 H, m, Ar-H), 9.93 (1
H, br.s., NH), 10.07 (1H, s, CHO).

C) 3-Bromo-5-methoxyindole-7-carbaldehyde The product of b) (40 mg, 0.22 mol) was dissolved in dichloromethane (5 ml) and treated with N-bromosuccinimide (40 mg), The mixture was stirred at room temperature for 16
Stir for hours. The solution was then diluted with dichloromethane, washed with water and brine, dried (MgSO _4), and evaporated. The residue is Kieselgel 60
Chromatography above, eluting with 0-50% ethyl acetate in hexane.
Fractions containing product were combined and evaporated to give the title compound as a pale pink solid (53 mg, 95%); δ _H (CDCl ₃ ) 3.94 (3H,
s, OMe), 7.34 (3H, s, 2-H, 4-H, 6-H), 9.93 (1H
, Br.s. NH), 10.06 (1H, s, CHO).

D) 2- [3- (3-Bromo-5-methoxy-1H-indol-7-ylmethylamino) prop-1-ylamino] -1H-quinazolin-4-one Polymer-supported CNBH ₃ was used, Using the above general reductive amination method,
The product of c) was coupled with Intermediate 2 on a 2 mmol scale to give the title compound as a white solid (31 mg, 34%); m / z (CI ⁺ ) 456 (MH ⁺ , 70%).
).

Example 9-2- [3- (3-Bromo-5-methoxy-1H-indole-7
-Ylmethylamino) prop-1-ylamino] -1H-thieno [3,2-d] pyrimidin-4-one Example 8 on the 0.15 mmol scale using the above general reductive amination method.
The product of c was coupled with Intermediate 3 to give the title compound as a white solid (15m
g, 22%); m / z (CI ⁺ ) 462 (MH ⁺ , 100%).

Example 10-2- [3- (3-chloro-5-methoxy-1H-indole-
7-ylmethylamino) prop-1-ylamino] -1H-quinazolin-4-one a) 3-chloro-5-methoxyindole-7-carbaldehyde The product of Example 8b (140 mg, 0.80 mmol) in dichloromethane. (1
0 ml), treated with N-chlorosuccinimide (105 mg) and the mixture was stirred at room temperature for 16 hours. The solution was then diluted with dichloromethane, washed with water and brine, dried (MgSO _4), then evaporated. The residue was chromatographed on Kieselgel 60, 0-50 in hexane.
Elute with% ethyl acetate. Fractions containing product were combined and evaporated to give the title compound as a pale pink solid (115 mg, 68%); δ _H (
CDCl ₃ ) 3.94 (3H, s, OMe), 7.28 (1H, d, J 2.5Hz)
, 7.33 (1H, d, J 2.4Hz), 7.39 (1H, d, J 2.4Hz),
9.93 (1H, br.s. NH), 10.06 (1H, s, CHO).

B) 2- [3- (3-chloro-5-methoxy-1H-indol-7-ylmethylamino) prop-1-ylamino] -1H-quinazolin-4-one Polymer-supported CNBH ₃ was used, Using the above general reductive amination method,
The product of a) was coupled with Intermediate 2 on a 15 mmol scale to give the title compound as a white solid (31 mg, 50%); m / z (CI ⁺ ) 412 (MH ⁺ , 80).
%).

Example 11-2- [3- (3-chloro-5-methoxy-1H-indole-
7-ylmethylamino) prop-1-ylamino] -1H-thieno [3,2-d] pyrimidin-4-one Using a polymer-supported cyanoborohydride, using the above general reductive amination method, The product of Example 10a was coupled with Intermediate 3 on a .2 mmol scale to give the title compound as a white solid (58 mg); m / z (CI ⁺ ) 418 (
MH ⁺ , 70%).

Example 12-2- [3- (3-chloro-5-methyl-1H-indole-7
-Ylmethylamino) prop-1-ylamino] -1H-thieno [3,2-d] pyrimidin-4-one dihydrochloride a) 5-methylindole-7-carbaldehyde as described for example 8a. 1- (tert-butoxycarbonyl)-
5-Methylindoline (J. Org Chem, 1999, 64, 3595; 2.9 g) was converted to 7-aldehyde. A portion of this product (1.5 mmol) was converted to the corresponding indole as described for Example 8b. The title compound was obtained as a yellow solid (167 mg, 64%); δ _H (CDCl ₃ ) 2.53 (3H, s, Me), 6.
56 (1H, dd, J = 2.2, 3.0Hz, 3-H), 7.30 (1H, t, J
= 3.0 Hz, 3-H), 7.47 (1H, d, J = 1.0 Hz, Ar-H), 7.
47 (1H, d, J = 1.0 Hz, Ar-H), 9.98 (1H, br.s., NH
), 10.10 (1H, s, CHO).

B) 3-Chloro-5-methylindole-7-carbaldehyde The product of a) (64 mg, 0.4 mm) as described for Example 10a.
of the title compound was obtained as a yellow solid (56 mg,
73%); δ _H (CDCl ₃ ) 2.55 (3H, s, Me), 7.25 (1H, t,
J = 3.2 Hz, 3-H), 7.45 (1H, s, Ar-H), 7.72 (1H, s)
, Ar-H), 9.87 (1H, br.s., NH), 10.10 (1H, s, CH).
O).

C) 2- [3- (3-chloro-5-methyl-1H-indol-7-ylmethylamino) prop-1-ylamino] -1H-thieno [3,2-d] pyrimidine-4-
On dihydrochloride Using polymer supported cyanoborohydride, the product of b was coupled with intermediate 3 on the 0.15 mmol scale using the general reductive amination method described above, then
Conversion to the corresponding dihydrochloride salt gave the title compound as a white solid (28 mg, 47
%); M / z (CI ⁺ ) 402 (MH ⁺ , 70%).

Example 13-2- [3- (3,5-Dibromo-2-ethylbenzylamino) prop-1-ylamino] -1H-pyrido [3,2-d] pyrimidin-4-one-2-hydrochloric acid Salt a) 3- (3-benzoylthioureido) pyridine-2-carboxylic acid ethyl ester 3-aminopyridine-2-carboxylic acid ethyl ester (1.3 g; Oakes et al
., J. Chem. Soc. 1956, 1045) was dissolved in acetone (50 ml) and benzoyl isothiocyanate (2.2 ml) was added. The solution was heated to reflux for 1 hour then cooled. The solution was concentrated in vacuo then methanol was added to the resulting oil to give a yellow precipitate. The solid was filtered to give the title compound (2.2g
, 82%). δ _H (d ₆ -DMSO) 1.30 (t, J = 7.0 Hz, 3 H), 4
.33 (q, J = 7.0 Hz, 2H), 7.56 (m, 2H), 7.68 (m, 2H)
), 8.00 (m, 2H), 8.43 (m, 1H), 8.58 (m, 1H), 11.
82 (br, 1H), 12.96 (br, 1H).

B) Potassium 1H-pyrido [3,2-d] pyrimidin-4-one-2-thiolate Similar to 3- (3-benzoylthioureido) pyridine-2 as for Intermediate 3a.
-Carboxylic acid ethyl ester (2.2 g) was treated to give the crude title compound which was used directly in the next step without further purification: (1.6 g) m / z (APCI).
) 180 (M + H ⁺ , 95%), 440 (100%).

C) 2-Methylsulfanyl-1H-pyrido [3,2-d] pyrimidin-4-one As for Intermediate 3b, crude 1H-pyrido [3,2-d] pyrimidin-4-one was obtained.
Treatment of potassium on-2-thiolate (1.6 g) gave the title compound (4
58 mg, 36% over steps (b) and (c)), m / z (APCI) 1.
94 (M + H ⁺ , 100%).

D) 2- (3-Aminopropylamino) -1H-pyrido [3,2-d] pyrimidin-4-one Similar to Intermediate 2, 2-methylsulfanyl-1H-pyrido [3,2- d
] Pyrimidin-4-one (450 mg) was treated to give the title compound (100 m
g, 19%). m / z (ESI) 218 ([M-H] ^- , 100%).

E) 2- [3- (3,5-dibromo-2-ethoxybenzylamino) prop-1-
Ilamino] -1H-pyrido [3,2-d] pyrimidin-4-one dihydrochloride According to the general reductive amination method described above, 2- (3-aminopropylamino) -1
H-pyrido [3,2-d] pyrimidin-4-one (90 mg) was added to 3,5-dibromo-
Reaction with 2-ethoxybenzaldehyde (126 mg) gave the title compound as an off-white solid (81 mg, 39%), m / z (ESI) 512 (
M + H ⁺ , 32%), 203 (100%).

Example 14-2- [3- (3,5-Dibromobenzylamino) prop-1-ylamino] -1H-pyrimido [4,5-d] pyrimidin-4-one Example 5 (334 mg) 2-Methylsulfanyl-1H-pyrimido [4,5-
Heated with d] pyrimidin-4-one (100 mg) at 85 ° C. for 18 hours.
The reaction mixture was purified by column chromatography to give the title compound as a pale yellow solid: (10mg, 4%). m / z (ESI) 469 (M + H ⁺ ,
100%).

Example 15-2- [3- (3,5-Dibromobenzylamino) prop-1-ylamino] -1H-thieno [2,3-d] pyrimidin-4-one dihydrochloride a) 2 2- (3-Benzoylthioureido) thiophene-3-carboxylic acid methyl ester 2-Aminothiophene-3-carboxylic acid methyl ester (2.4 g; Gewald, Chem. Ber. 1965, 98, 3571-3577, analogously to 13a. ) Was processed to give the title compound as an off-white solid (3.6 g, 74%). m / z 319 (
M + H ⁺ , 100%).

B) 1H-thieno [2,3-d] pyrimidin-4-one-2-thiolate potassium In the same manner as for the intermediate 3a, 2- (3-benzoylthioureido) thiophene-
Treatment of 3-carboxylic acid methyl ester (2.9 g) gave the crude title compound containing benzoate: desired product 1: 1 (1.2 g). δ _H (d ₄ -Me
OH) 6.36 (m, 1H), 6.58 (m, 1H); and the crude product was used in the next step.

C) 2-Methylsulfanyl-1H-thieno [2,3-d] pyrimidin-4-one Treat the crude material of step b) as for Intermediate 3b to give a crude off-white solid. The title compound was obtained and used without further purification: (90
6 mg), m / z (APCI) 199 (M + H ⁺ , 100%).

D) 2- [3- (3,5-Dibromobenzylamino) prop-1-ylamino]-
1H-thieno [2,3-d] pyrimidin-4-one dihydrochloride Example 5a (190 mg) was treated with 2-methylsulfanyl-1H-thieno [2,3-
Heated at 125 ° C. for 26 hours with d] pyrimidin-4-one (60 mg).
The reaction mixture was purified by column chromatography and the product was converted to the corresponding dihydrochloride salt using concentrated HCl in methanol to give the title compound as an off-white solid (50 mg, 31%). ). m / z (ESI) 473 (M
+ H ⁺ , 100%).

Example 16-2- [3- (3,5-dichloro-2-ethoxybenzylamino)
Propa-1-ylamino] -1H-quinazolin-4-one dihydrochloride a) 3,5-dichloro-2-ethoxybenzaldehyde 3 on a 5.2 mmol scale using the above general phenol alkylation method. Alkylation of 5,5-dichloro-2-hydroxybenzaldehyde gave the title compound as a yellow solid (1.14 g, 99%); m / z (ES ⁺ ) 219.
(MH ⁺ , 70%).

B) 2- [3- (3,5-dichloro-2-ethoxybenzylamino) prop-1-
Ilamino] -1H-quinazolin-4-one dihydrochloride According to the above general reductive amination method, 3,5-dichloro-2-ethoxybenzaldehyde (44 mg) was reacted with intermediate 2 (44 mg) to give off. The title compound was obtained as a white solid (29 mg, 29%). m / z (ESI) 42
1 (M + H ⁺ , 9%), 202 (100%).

Example 17-2- [3- (3,5-dibromo-2-ethoxybenzylamino)
Propa-1-ylamino] -1H-thieno [3,2-d] pyrimidin-4-one dihydrochloride 3,5-dibromo-2-ethoxybenzaldehyde (92 mg) was added according to the above general reductive amination method. Reaction with Intermediate 3 (89 mg) gave the title compound as an off-white solid (58 mg, 33%), m / z (ESI) 208.
(100%), 517 (M + H ⁺ , 25%).

Example 18-2- [3- (6-Chloro-8-iodocroman-4-ylamino) prop-1-ylamino] -1H-thieno [3,2-d] pyrimidin-4-one-2-di Hydrochloride 6-chloro 8-iodocroman-4-one (300 mg) and intermediate 3 (2
89 mg) was dissolved in 3% v / v acetic acid in methanol (10 ml) and sodium methoxide (104 mg) was added. Sodium cyanoborohydride (122m
g) was added and the reaction mixture was heated at 80 ° C. for 24 hours. The mixture was evaporated in vacuo and the residue was purified by column chromatography. The product was converted to the corresponding dihydrochloride salt using concentrated HCl in methanol to give the title compound as an off-white solid (20 mg, 4%), m / z (ESI) 5
17 (M + H ⁺ , 100%).

Example 19-2- [3- (6,8-Dibromochroman-4-ylamino) prop-1-ylamino] -1H-thieno [3,2-d] pyrimidin-4-one dihydrochloride 6,8-Dibromochroman-4 according to the method used for Example SA6.
-One (WO 00 /, see SmithKline Beecham) (92 mg) was reacted with the dihydrochloride salt of Intermediate 3 (89 mg) to give the title compound as a white solid (9 mg, 5%). m / z (ESI) 515 (M + H +, 25%).

Example 20-2- [3- (6-Bromo-8-chloro-1,2,3,4-tetrahydroquinolin-4-ylamino) prop-1-ylamino] -1H-quinazolin-4-one Dihydrochloride 6-Bromo-8-chloro-2,3-dihydro-1H-quinolin-4-one (WO
00 /, see SmithKline Beecham) (40 mg) and Intermediate 2
The dihydrochloride salt of (45 mg) was dissolved in 3% v / v acetic acid (5 ml) in methanol.
Sodium cyanoborohydride (50 mg total) was added and the reaction mixture was added to 85
Heated to ° C for a total of 76 hours. The reaction mixture was passed through a cation exchange cartridge and the residue was purified by column chromatography. Conversion of the product to the corresponding dihydrochloride salt using concentrated HCl in methanol gave the title compound as an off-white solid (4 mg, 4%), m / z (ESI) 462 ([
M-H] ^- , 100%).

Example 21-2- [3- (6-Ethyl-8-iodo-1,2,3,4-tetrahydroquinolin-4-ylamino) prop-1-ylamino] -1H-quinazolin-4-one Dihydrochloride 6-Ethyl-8-iodo-2,3 according to the method used for Example 20.
-Dihydro-1H-quinolin-4-one (WO 00 /, see Smithkline Beecham) (60 mg) was reacted with the dihydrochloride salt of Intermediate 2 (58 mg),
The title compound was obtained as an off-white solid (10 mg, 8%). m / z (E
SO) 504 (M + H ⁺ , 15%), 286 (100%).

Example 22-2- [3- (6,8-Dibromo-1,02,3,4-tetrahydroquinolin-4-ylamino) prop-1-ylamino] -1H-thieno [3,2-
d] Pyrimidin-4-one dihydrochloride According to the method used for Example 18, 6,8-dibromo-2,3-dihydro-1H-quinolin-4-one (304 mg) was dihydrochloride of Intermediate 3. (149m
g) to give the title compound as an off-white solid (13 mg,
4%). m / z (ESI) 514 (M + H ⁺ , 100%).

Example 23-2- [3- (6,8-Dibromo-1,2,3,4-tetrahydroquinolin-4-ylamino) prop-1-ylamino] -1H-quinazolin-4-one.di Ensanen According to the method used for Example 20, 6,8-dibromo-2,3-dihydro-1H-quinolin-4-one (52 mg) was added to the dihydrochloride of intermediate 2 (58 mg).
Was reacted with to give the title compound as an off-white solid (1 mg, 1%).
, M / z (ESI) 508 (M + H ⁺ , 100%).

[0105]   Example 24-2- [3- (6-Bromo-8-methoxy-1,2,3,4-tetra
Hydroquinolin-4-ylamino) prop-1-ylamino] -1H-quinazoline
-4-on   a) 3- (2-methoxy-4-bromophenylamino) propionic acid   3- (2-methoxyphenylamino) dissolved in dry DMF (20 ml) at 0 ° C
Propionic acid (J. Chem. Soc., Perkin 1, 1972, 932; J. Med. Chem., 1965, 8
, 566; 1.95 g, 10 mmol) was recrystallized from N-bromosuccinide (1.7).
8 g, 10 mmol). After stirring for 4 hours at room temperature, evaporate the DMF
, The residue was partitioned between diethyl ether (50 ml) and water (50 ml)
. The organic layer was separated, washed with water, dried and evaporated to give a brown solid.
The compound was obtained. δ (CDCl3 + D2O) 2.68 (2H, t, J = 6.4Hz)
3.46 (2H, t, J = 6.8Hz), 3.82 (3H, s), 6.48 (1H
, D, J = 8.4 Hz), 6.85 (1 H, d, J = 2 Hz), 6.97 (1 H,
dxd, J = 2 & 8.4 Hz); MS AP⁻272^Br79(100%) MH
⁻.

B) 6-Bromo-8-methoxy-2,3-dihydro-1H-quinolin-4-one At 100 ° C., 3 parts of a mixture of phosphorus pentoxide (35 g) in 85% phosphoric acid (15 ml) was added.
-(2-Methoxy-4-bromophenylamino) propionic acid (1 g, 3.65 m
mol) was added. After 1 hour, the dark red mixture obtained was poured onto ice and the aqueous solution was made alkaline by careful treatment with concentrated ammonium hydroxide. The organic material was extracted with ethyl acetate (3 x 50 ml) and the combined organic phases were washed with saturated sodium carbonate solution. The organic phase was separated, dried and evaporated to give the title compound as a light yellow solid. δ (CDCl ₃ ) 2.70 (2H, t, J = 6
.8Hz), 3.60 (2H, dxt, J = 2.4 & 7.1Hz), 3.87 (3
H, s), 4.92 (1H, brd. S), 6.90 (1H, d, J = 2Hz),
7.59 (1H, d, J = 2Hz); MS AP ⁺ 256 ^Br79 (100%) M
H +.

C) 2- [3- (6-Bromo-8-methoxy-1,2,3,4-tetrahydroquinolin-4-ylamino) prop-1-ylamino] -1H-quinazolin-4-one 6- Bromo-8-methoxy-2,3-dihydro-1H-quinolin-4-one (
85 mg, 0.33 mmol), dihydrochloride of intermediate 2 (58 mg, 0.2 mmol)
) And sodium acetate (32.8 mg, 0.4 mmol) in 3% acetic acid in methanol (5 ml) heated at reflux for 1 hour, cooled and added sodium cyanoborohydride (20 mg, 0.32 mmol). did. After refluxing for a further 48 hours, the mixture was calibrated and the solvent was evaporated. The crude product was chromatographed on silica gel eluting with a dichloromethane-methanol-ammonium hydroxide mixture to give the free base. Treated with 1M methanolic hydrogen chloride,
The title compound was obtained as a cream solid. δ (CD ₃ OD) 1.78-1.93
(2H, m), 2.82 (2H, t, J = 6.84Hz), 3.21-3.43 (6
H, m), 3.75 (3H, s), 3.54-3.55 (1H, m), 6.76 (1
H, d, J = 2Hz), 6.92 (1H, d, J = 1.6Hz), 7.18 (1H
, J = 7.12 Hz), 7.23 (1H, d, J = 8.32 Hz), 7.59 (1H
, T, J = 7.0 Hz), 7.98 (1H, d, J = 8.1 Hz); MS ES ^- 4.
56 ^Br79 (100%) [MH]-.

Example 25-2- [3- (4,5-Dibromo-3-methylthien-2-ylmethylamino) prop-1-ylamino] -1H-thieno [3,4-d] pyrimidine-4- On dihydrochloride a) 2-Methylsulfanyl-1H-thieno [3,4-d] pyrimidin-4-one 4-aminothiophene-by passing through a column of alumina and eluting with 10% methanol in dichloromethane. The 3-carboxylic acid methyl ester was released from the hydrochloride salt. Treatment of the free amine (4g) as for Examples 13a-13c gave the title compound (520mg, 10% over 3 steps). δ _H (d ₆ -DMSO) 2.49 (br, 3H), 7.60 (m, 1H), 8.40 (m, 1)
H), 12.0 (br, 1H).

B) 2- (3-Aminopropylamino) -1H-thieno [3,4-d] pyrimidin-4-one 2-methylsulfanyl-1H-thieno [3,4-d] pyrimidin-one at 0 ° C. 4-
On (310 mg) was suspended in dioxane and hydrogen peroxide solution (3% w / H ₂ O /
w, 3.5 ml) was added, followed by acetic acid (5 drops) and a catalytic amount of methyltrioxorhenium. After stirring for 90 minutes at 25 ° C., the yellow liquid was treated with MnO ₂ , filtered through Celite and evaporated in vacuo. The crude product was purified by heating with 1,3-diaminopropane (0.63 ml) at 80 ° C. for 18 hours and column chromatography to give a fraction containing the title compound, which was further purified. Used without purification (100 mg). m / z (APCI)
225 (M + H ⁺ , 35%), 208 (100%).

C) 5-Bromo-3-methylthiophene-2-carboxaldehyde 3-Methylthiophene-2-carboxaldehyde (5 g, 39.6 mmol)
Was dissolved in dry chloroform (100 ml) and the solution was cooled to 0 ° C. Bromine (6.33 g, 39.6 mmol) was added dropwise and then the reaction was stirred at room temperature for 16 hours. The solution was diluted with chloroform and washed with 1M aqueous sodium carbonate solution and water. The organic solution was dried and evaporated. The residue is Kieselgel 6
Chromatography on 0, eluting with 1: 1 dichloromethane-hexane. Fractions containing product were combined and evaporated to give the title compound as a yellow solid (7.5g, 92%). δH (CDCl ₃ ) 2.53 (3H, s, C
_{H 3), 6.96 (1H,} s, Ar-H), 9.9 (1H, s, CHO).

D) 4,5-Dibromo-3-methylthiophene-2-carbanedehyde 5-Bromo-3-methylthiophene-2-carboxaldehyde (7.5 g,
36.5 mmol) in dry chloroform (75 ml), aluminum trichloride (12.2 g, 91.42 mmol) is added and the reaction mixture is stirred for 5 minutes before bromine (5.84 g, 36.5 mmol). Was added. The reaction at room temperature for 16
Stir for hours, dilute with chloroform, and wash with aqueous sodium bicarbonate and water. The organic solution was dried and evaporated. The residue was chromatographed on Kieselgel 60, eluting with dichloromethane. Fractions containing product were combined and evaporated to give the title compound as a pale yellow solid (7.
02g, 70%). δ _H (CDCl ₃ ) 1.53 (3H, s, CH ₃ ), 9.93
(1H, s, CHO).

E) 2- [3- (4,5-dibromo-3-methylthien-2-ylmethylamino)
Propa-1-ylamino] -1H-thieno [3,4-d] pyrimidin-4-one dihydrochloride According to the above general reductive amination method, 4,5-dibromo-3-methylthiophene-2-carbo The aldehyde (70 mg) was reacted with the product of b) (50 mg) to give the title compound as an off-white solid (20 mg, 16%). m
/ Z (ESI) 492 (M + H ⁺ , 100%).

Example 26-2- [3- (4,5-dibromothien-2-ylmethylamino)
Propa-1-ylamino] -1H-quinazolin-4-one dihydrochloride According to the above general reductive amination method, 4,5-dibromothien-2-carbaldehyde (54 mg, 0.2 mmol) was added to Intermediate 2 (43 mg, 0.2 mmol
) To give the title compound as a white solid (29 mg, 26%). MS
(ES ⁺ ) 471/473/475 (12/24/13%) MH ⁺ , 253/2
55/257 (50/100/50%).

Example 27-2- [3- (4,5-dibromothien-2-ylmethylamino)
Propa-1-ylamino] -1H-thieno [3,2-d] pyrimidin-4-one dihydrochloride 3,4-dibromothiophene-2-carbaldehyde (54 mg, according to the general reductive amination method above. 0.2 mmol) as intermediate 3 (45 mg, 0.2 mm)
ol) to give the title compound as a white solid (17 mg). MS E
S ⁺ 478 (27%) MH ⁺ .

Example 28-2- [3- (4,6-Dichloro-1H-indol-2-ylmethylamino) prop-1-ylamino] -1H-quinazolin-4-one dihydrochloride 4,6-dichloro-1H-indole-2-carbaldehyde (WO 99/55677; 150 mg) according to various reductive amination methods to intermediate 2 (153 mg).
) To give the title compound as an off-white solid (130 mg, 3
8%. m / z (ESI) 416 (M + H ⁺ , 100%).

Example 29-2- [3- (4,6-Dichloro-1H-indol-2-ylmethylamino) prop-1-ylamino] -1H-thieno [3,2-d] pyrimidine-4- On dihydrochloride According to the general reductive amination method described above, 3,4-dichloro-1H-indole-2-carbaldehyde (WO 99/55677; 150 mg) was added to the dihydrochloride of Intermediate 3 (
208 mg) to give the title compound as a white solid (65 mg, 19%
). m / z (ESI) 422 (M + H ⁺ , 100%).

Example 30-2- {3- [3,5-Dibromo-2- (3-morpholinopropoxy) benzylamino] -prop-1-ylamino} -1H-quinazolin-4-one trihydrochloride a ) 3,5-Dibromo-2- (3-morpholinopropoxy) benzaldehyde 3,5-dibromo-2-vitroxybenzaldehyde (2.80 g), N- (3
-Chloropropyl) morpholine hydrochloride (2.00 g; Schliemann, W .; Buege, A
Reppel, L. Pharmazie 1980, 35, 69-72), a mixture of tetra-n-butylammonium iodide (0.74 g), potassium carbonate (1.52 g) and N, N-dimethylformamide (15 ml). The mixture was stirred at room temperature for 1 hour and then at 60 ° C. for 16 hours. The mixture was then partitioned between water and ethyl acetate. The organic layer was washed (aq. NaHCO ₃ , brine) and concentrated to give the title compound as an orange oil in sufficient purity for the next step (4.76 g). m / z (ESI) 406
(MH ⁺ , 32%).

B) 2-{-[3,5-Dibromo-2- (3-morpholinopropoxy) benzylamino] prop-1-ylamino} -1H-quinazolin-4-one trihydrochloride General reduction as described above According to the amination method, 3,5-dibromo-2- (3-morpholinopropoxy) benzaldehyde (105 mg) was reacted with Intermediate 2 (44 mg). The product was isolated by column chromatography, treated with excess HCl in methanol, volatiles were evaporated, the residue was dissolved in water and lyophilized to give the title compound as a colorless solid ( 88 mg). m / z (ESI) 61
0 (MH ⁺ , 76%).

Example 31-2- {3- [3,5-dibromo-2- (3-morpholinopropoxy) benzylamino] -prop-1-ylamino} -1H-thieno [3,2-d] pyrimidine- 4-one trihydrochloride Example 30a (105 mg) was reacted with Intermediate 3 (45 mg) according to the general reductive amination procedure described above. The product was isolated by column chromatography, treated with excess HCl in methanol, volatiles were evaporated, the residue was dissolved in water and lyophilized to give the title compound as a colorless solid. (74 mg)
. m / z (ESI) 616 (MH ^<+> , 57%).

Example 32-2- {3- [4,6-dichloro-1- (2-hydroxyethyl)
-1H-Indol-2-ylmethylamino] prop-1-ylamino} -1H-
Thieno [3,2-d] pyrimidin-4-one a) 4,6-dichloro-1- (methoxycarbonylmethyl) -1H-indole-2-carboxylic acid ethyl ester 4,6-dichloro-1H-indole-2 -Carboxylic acid ethyl ester (0.5
16 g, 2 mmol) was dissolved in DMF (5 ml) and then potassium carbonate (0
.276 g, 2 mmol) was added. The mixture was stirred under argon for 30 minutes, then methyl bromoacetate (0.19 ml, 2 mmol) was added. The mixture was stirred for a further 2.5 hours, then diluted with water and extracted with diethyl ether. The combined organic extracts were washed with brine, dried and evaporated to give the title compound as a beige powder (0.65g, 98%); MS (APCI + ve
) 330, 332 (30, 21%, MH ⁺ ).

B) 2- (4,6-Dichloro-2-hydroxymethyl-1H-indole-1-
Yl) ethanol 4,6-dichloro-1- (methoxycarbonylmethyl) -1H-indole-2
-Carboxylic acid ethyl ester (0.625 g, 1.89 mmol) in THF (20
ml), cooled in an ice / salt bath under argon and slowly treated with a solution of lithium aluminum hydride (1M in THF, 2.27 ml, 2.27 mmol). The mixture was stirred for 2 hours, then carefully quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with brine and evaporated to give the crude product as an oily solid (0.5g, q). This material was used without further purification.

C) 4,6-Dichloro-1- (2-hydroxyethyl) -1H-indole-2
-Carboxaldehyde The crude material from b) above (about 1.89 mmol) was dissolved in dichloromethane (50 ml), manganese dioxide (1.64 g, 18.9 mmol) was added and the mixture was stirred for 3.5 hours. The mixture was filtered, washed well with dichloromethane and 1,4-dioxane, then evaporated to give a solid. This moisture was dissolved in dichloromethane, pre-absorbed on silica, then purified by flash chromatography, eluting with 0-20% ethyl acetate in 40-60 petroleum ether and titled as a white powder. The compound was obtained (0.203 g, 39%). MS (A
PCI-ve) 257, 259 (100, 66%, MH-).

D) 2- {3- [4,6-dichloro-1- (2-hydroxyethyl) -1H-indol-2-ylmethylamino] prop-1-ylamino} -1H-thieno [3,2
-D] Pyrimidin-4-one The product of c) was reacted with Intermediate 3 according to the general reductive amination procedure described above to give the title compound as a white powder (0.03g, 32%). LC / MS (ES
+) 466,468 (15,10%, MH ^<+> ).

Actual command 33-2- [3- (2-ethoxy-5-iodo-3-methylbenzylamino) prop-1-ylamino] -1H-quinazolin-4-one a) 2-hydroxy-5-yohedo -3-Methylbenzaldehyde 2-hydroxy-3-methylbenzaldehyde (272 mg, 2.0 mmol
) Was dissolved in dimethylformamide (10 ml) and sodium iodide (360 m
g, 2.4 mmol), then chloroamine T (546 mg, 2.4 m
mol). After stirring at room temperature for 4 hours, the suspension was treated with water and treated with 1N.
Acidified with HCl and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 5% solution of sodium thiosulfate, brine, then dried and evaporated.
The residue was chromatographed on Kieselgel 60, eluting with 0-50% toluene in hexane. Fractions containing product were combined and evaporated to give the title compound as a white solid (330mg, 63%). m / z (A
P ⁻ ) 261 ([M−H] ⁻ , 20%).

B) 2-Ethoxy-5-iodo-3-methylbenzaldehyde 2-on a 1.2 mmol scale using the general phenol alkylation method.
Hydroxy-5-iodo-3-methylbenzaldehyde was alkylated to give the title compound as a white solid (350mg, 100%). δ _H (CDCl ₃ ) 1.
43 (3H, t, J = 7.0Hz, CH 3), 2.29 (3H, s, CH 3), 3
.99 (2H, q, J = 7.0Hz, OCH 2), 7.64 (1H, d, J = 2.3
Hz, Ar-H). 7.96 (1H, d, J = 2.3Hz, Ar-H), 10.25
(1H, s, CHO).

C) 2- [3- (2-Ethoxy-5-iodo-3-methylbenzylamino) prop-1-ylamino] -1H-quinazolin-4-one Using general reductive amination method 2-ethoxy-on a 0.2 mmol scale
5-Iodo-3-methylbenzaldehyde was coupled with Intermediate 2 to give the title compound as a white solid (66mg, 67%). m / z (ES ⁺ ) 493 (MH ⁺ , 100%).

Example 34-5- [3- (3,4-Dichlorobenzylamino) prop-1-ylamino] -4H-thieno [3,4-b] pyridin-7-one dihydrochloride a) 2 -[3- (3,4-Dichlorobenzylamino) prop-1-ylamino]-
4-Methoxythieno [3,4-b] pyridine 2-chloro-4-methoxythieno [3,4-b] pyridine (0.13 g; Barker e
t al., J. Chem. Res. Miniprint 1989, 7, 1501-1523) and Intermediate 1 (0.4)
ml) was heated at 120 ° C. for 16 hours with stirring. The product was subjected to column chromatography, 6-10% in CH ₂ Cl ₂ [10: 1 MeOH / conc NH ₃ (
Aqueous solution)] to give the title compound as a brown oil (40 mg). m / z (ESI) 419 (M + Na ⁺ , 20%).

B) 5- [3- (3,4-dichlorobenzylamino) prop-1-ylamino]-
4H-thieno [3,4-b] pyridin-7-one dihydrochloride 2- [3- (3,3,3 in dioxane (0.5 ml) and concentrated aqueous HCl (5 ml).
4-dichlorobenzylamino) prop-1-ylamino] -4-methoxythieno [
3,4-b] Pyridine (40 mg) was heated in a 120 ° C. oil bath for 16 hours. Dioxane (2 ml) was added and heating continued for 7 hours. The volatiles were then evaporated, the residue triturated with chloroform, the solid collected by filtration and further subjected to column chromatography, 10-25% in CH ₂ Cl ₂ [10: 1 M.
eOH / conc. NH ₃ (aq)]. The oil thus obtained was treated with excess HCl in methanol, the volatiles were evaporated and the residue was triturated with chloroform to give the title compound as an off-white solid after filtration (18 mg). m / z (ESI) 404 (M + Na ⁺ , 13%); 38
2 (M + H ⁺ , 20%).

Biological data 1. Enzyme Inhibition-Aminoacylation Assay The compounds of the present invention were prepared using the enzyme methionyl tRNA synthase (MRS) as follows.
) Can be assayed using recombinant Staphylococcus aureus MRS.

Reaction mix (per ml) Stock volume (ul) Final concentration 100 mM Tris / Cl 600 30 mM (pH 7.9) 250 mM KCl 75 mM 125 mM ATP 40 2.5 mM 250 mM MgCl ₂ 80 10 mM 50 mM DTT 80 2 mM 0.5 mM Met 40 10 μM (S-35 hot and cold) Solid tRNA 4 mg / ml 2 mg / ml (mixture with E. coli MRE600) H ₂ O 160 2 mg / ml 10x inhibitor 5 μl / well 0-10 μM (0-100 μM)

The reaction is started by adding 20 μl of appropriately diluted pure enzyme (pre-incubated with the inhibitor) to 25 μl of the reaction mixture for 10 minutes at room temperature.
The reaction is terminated by adding 100 μl of 5% trichloroacetic acid, 10% glycerol. Packard Filtermathe cell harvester
Dry TCA precipitate using te Cell Harvester)
Harvest on GFC plates. The filters are washed with 4 × 200 μl of 50% technical methyl alcohol and dried. 30 μl of Microscint
Add to each well and add the plate to TopCount (Packard 96
Calculated on the well counter)

[0132] The mixture of reagents E. coli MRE600tRNA and ATP Boehringer - was purchased from Mannheim, the L- ^[35 S] methionine from Amersham, was purchased other reagents from Sigma. Pure recombinant Staphylococcus aureus MRS (EP application no. 9730)
(0317.1, SmithKline Beecham) was obtained using standard purification methods. The enzyme is diluted in Dilution Buffer consisting of 10 mM Tris / Cl, 2 mM DTT (pH 7.9).

Results Examples 1-34 have IC ₅₀ values for Staphylococcus aureus MRS of <3 to 800 nM. All compounds have a high selectivity for mammalian enzymes (up to 1 μM did not inhibit rat MRS).

2. Antibacterial activity Compounds of the present invention were tested in a standard MIC assay, where they were modified by the addition of cyclodextrin to improve solubility, and a series of pathogenic organisms (S. aureus, S. pneumoniae, E. faecalis, Antibacterial activity against H. influenzae and strains of M. catarrhalis) was assayed. The compounds of Examples 1, 3, 5, 6, 8-12, 16-25 and 27-33 are:
Against the stocks of S. aureus, S. pneumoniae and E. faecalis,
<1 μg / ml MIC; and 2-> 64 against M. catarrhalis
It had a MIC in the μg / ml range. Examples 28 and 29 were active against etch influence.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 31/04 A61P 31/04 C07D 403/12 C07D 403/12 471/04 117 117 471/04 117Z 487/04 143 487/04 143 148 148 495/04 105 105 495/04 105A 105Z (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, T ), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI , GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA , UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Surah Ann Armstrong United Kingdom, CM 19.5 ADA, Essex, Harlow, Third Avenue, New Frontiers Science・ Park South, Miss Crane Beatham Pharmaceuticals (72) Inventor John Michael Berg United Kingdom, CM 19.5 ADO, Essex, Harlow, Third Avenue, New Frontiers Science Park South, Smith Klein Beecham Pharmaceuticals (72) Inventor Pamela Brown United Kingdom, CM 19.5 ADA, Essex, Harlow, Third Avenue, New Frontiers Science Park South, Smith Cline・ Beachum Pharmaceuticals (72) Inventor John Stephen Elder Cm 19.5 ADA, Essex, Harlow, Third Avenue, New Frontiers Science Park Sau, UK S. Smith Crane Beecham Pharmaceuticals (72) Inventor Andrew Keith Forest United Kingdom, CM 19.5 AD, Essex, Harlow, Third Avenue, New Frontiers Science Park South, Smith Crane Beatham Pharmaceuticals (72) Inventor Dieter Wolfgang Humprecht, UK 19.5 ADA, Essex, Harlow, Third Avenue, New Frontiers Science Park South, Smith Crane Beatham Pharmaceuticals (72) Inventor Richard Lewis Jarvest UK 19.5 ADA, Essex, Harlow, Third Avenue, New Flo Tears Science Park South, Smith Crane Beecham Pharmaceuticals F-Term (reference) 4C050 AA01 BB05 BB08 CC08 EE04 FF01 GG03 GG04 HH01 4C063 AA01 BB09 CC31 DD06 EE01 4C065 AA04 BB11 CC01 DD03EE02 PP03 4C071 AA01 BB01 CC01 CC02 CC21 DD11 DD12 EE13 FF05 FF06 HH08 HH17 JJ01 LL01 4C086 AA01 AA02 AA03 BC46 CB05 CB06 CB09 CB10 CB27 GA07 MA01 MA04 NA14 ZB35

Claims (16)

[Claims] 1. Formula (I): [Wherein W is CH and R ¹ is a residue of a 5- or 6-membered heteroaryl ring,
Alternatively, W is N and R ¹ is the residue of a 5- or 6-membered heteroaryl ring or aryl ring, wherein heteroaryl or aryl ring is halo, cyano, hydroxy, C _{(1-6 )} Alkyl (optionally substituted by halo, hydroxy, amino, mono or perfluoro C _(1-3) alkyl, carboxy or C _(1-6) alkoxycarbonyl) C _(3-7) cycloalkyl, C _{(1 -6)} Alkoxy, amino, mono- or di-C _(1-6) alkylamino, acylamino, carboxy, C _(1-6) alkoxycarbonyl, carboxy C _(1-6) alkyloxy, C _{(1-6) Alkylthio} , C _(1-6) alkylsulfinyl, C _{(
1-6) selected from} alkylsulfonyl, sulfamoyl, mono- and di-C _(1-6) alkylsulfamoyl, carbamoyl, mono- and di-C _(1-6) alkylcarbamoyl, and heterocyclyl. ~ Is optionally substituted with 3 substituents); R ² is an optionally substituted aryl or an optionally substituted heteroaryl ring; X is CH ₂ or CHR ³ ( Here, R ³ is C _(1
-6) Alkyl, or R ³ may be attached to the ortho position of the aryl or heteroaryl ring of R ² and contain oxygen or nitrogen as ring atoms 5
~ May form a 7-membered ring); Y is C _(1-3) alkylene or C _(4-6) cycloalkylene], and the pyrimidone ring (when W is N) Compounds, including variants, and salts thereof, preferably pharmaceutically acceptable salts. 2. The formula (I) according to claim 1, wherein R ¹ is a ring residue in which the heteroatom is sulfur, for example thieno, or a ring residue in which the nitrogen is nitrogen, for example pyrido and pyrazolo. The compound shown. 3. The compound of formula (I) according to claim 1 or 2, wherein R ¹ is a ring residue selected from thieno, pyrido and pyrazolo. 4. X is CH ₂ or forms a 5 to 7 membered ring containing oxygen or nitrogen as a ring atom, which is condensed with an aryl ring or a heteroaryl ring together with R ^2. A compound represented by formula (I) according to any one of the above. 5. When R ² is aryl it is selected from phenyl and naphthyl optionally substituted with up to 4 substituents and when it is heteroaryl it is substituted with up to 3 substituents. A compound of formula (I) according to any one of claims 1 to 4 selected from optionally substituted pyrrolyl, thienyl, furanyl, pyridyl, quinolinyl, benzofuranyl and indolyl. 6. The aryl and heteroaryl groups for R ² are each:
A compound of formula (I) according to claim 5 which is phenyl and indolyl. 7. R ² X is benzyl, chroman-4yl, 1,2,3,4-tetrahydroquinolin-4-yl, indol-2-ylmethyl, and thien-2.
A compound of formula (I) according to any one of claims 1 to 4, which is -ylmethyl (wherein the aryl / heteroaryl is optionally substituted). 8. A compound represented by the formula (I) according to any one of claims 1 to 7, wherein Y is a C ₂ alkylene chain. 9. Formula (IA), or formula (IB), which is a second set of pyrimidone compounds wherein W is N: [Chemical 3] The compound according to any one of claims 1 to 8 10. A compound of formula (I) according to claim 1 selected from the title compounds of Examples 1-34. 11. 2- [3- (3-Bromo-5-methoxy-1H-indol-7-ylmethylamino) prop-1-ylmino] -1H-quinazolin-4-one; 2- [3- ( 3-Bromo-5-methoxy-1H-indol-7-ylthymeramino) prop-1-ylamino] -1H-thieno [3,2-d] pyrimidin-4-one; 2- [3- (3-chloro -5-methoxy-1H-indol-7-ylmethylamino) prop-1-ylamino] -1H-quinazolin-4-one; 2- [3- (3-chloro-5-methoxy-1H-indole-7- Ilmethylamino) prop-1-ylamino] -1H-thieno [3,2-d] pyrimidin-4-one; 2- [3- (3-chloro-5-methyl-1H-indol-7-ylmethylamino ) Propa-1-ylamino] -1H-thieno [3, -d] pyrimidin-4-one; 2- [3- (6-Chloro-8-iodochroman-4-ylamino) prop-1
Ilamino] -1H-thieno [3,2-d] pyrimidin-4-one; 2- [3- (6,8-dibromochroman-4-ylamino) prop-1-ylamino] -1H-thieno [3,2 -D] pyrimidin-4-one; 2- [3- (6-bromo-8-chloro-1,2,3,4-tetrahydroquinoline-
4-ylamino) prop-1-ylamino] -1H-quinazolin-4-one; 2- [3- (6,8-dibromo-1,2,3,4-tetrahumancelloquinolin-4-ylamino) proper 1-ylamino] -1H-thieno [3,2-d] pyrimidine-4
2- [3- (6,8-dibromo-1,2,3,4-tetrahydroquinolin-4-ylamino) prop-1-ylamino] -1H-quinazolin-4-one; 2- [3- (4,6-Dichloro-1H-indol-2-ylmethylamino) prop-1-ylamino] -1H-quinazolin-4-one; 2- [3- (4,6-dichloro-1H-indole-2- Ilmethylamino) prop-1-ylamino] -1H-thieno [3,2-d] pyrimidin-4-one; 2- {3- [3,5-dibromo-2- (3-morpholinopropoxy) benzylamino] -Prop-1-ylamino} -1H-quinazolin-4-one; 2- {3- [4,6-dichloro-1- (2-hydroxyethyl) -1H-indol-2-ylmethylamino] prop-1 -Ilamino} -1H-thieno [3,2-d
] Pyrimidin-4-one; and 2- [3- (2-ethoxy-5-iodo-3-methylbenzylamino) proper
A compound of formula (I) according to claim 10 selected from 1-ylamino] -1H-quinazolin-4-one. 12. A pharmaceutical composition comprising an antibacterial effective amount of the compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier or excipient. 13. A compound of formula (I) according to claim 1 for therapeutic use. 14. A compound of formula (I) according to claim 1 for the treatment of bacterial infections. 15. The formula (1) of claim 1 in the manufacture of a medicament for the treatment of bacterial infections.
Use of a compound represented by I). 16. A method for producing a compound represented by formula (I), which comprises:
): [Chemical 4] [Wherein R ¹ , W and Y are the same as defined above], (a) for the compound of formula (I) wherein X is CH ₂ , under reductive alkylation conditions: Formula (III): R ² CHO (III) [wherein R ² is the same as the above definition], (b) CH ₂ in which X is substituted with C _(1-6) alkyl Or a compound of formula (I) wherein R ² and X are linked by a 5 to 7 membered ring which may contain oxygen or nitrogen, under the conditions of reductive alkylation: )
R ² R ³ CO (IV) [wherein R ² and R ³ are the same as defined above], or (c) the compound represented by the formula (IB) Formula (V) under nucleophilic substitution conditions: [Wherein R ¹ is the same as defined above, and R ⁴ is a leaving group, for example, halo, for example, chloro, or C _(1-6) alkylthio]. ): R ² XNHYCH ₂ NH ₂ (VI) [wherein R ² , X and Y are the same as defined above] or (d) a compound represented by the formula (IA) ), A compound of formula (VII)
: [Chemical formula 6] [Wherein R ¹ is the same as defined above, R ⁵ is a leaving group such as halo, for example chloro, and R ⁶ is C _(1-6) alkyl, such as methyl or ethyl, Or an aryl C _(1-4) alkyl group] is reacted with an amine of formula (VI) or an active derivative thereof as defined above to form an intermediate, followed by acidic hydrolysis. According to formula (IA)
A method comprising converting to a compound represented by: