HK1110867A

HK1110867A - Selected benzofuran derivatives

Info

Publication number: HK1110867A
Application number: HK08105531.7A
Authority: HK
Inventors: 索拉努．格赖弗勒丁格-波纳鲁; 哈立德．伊斯兰; 迪特尔．吉勒森; 卡斯帕．布里
Original assignee: 阿皮德公开股份有限公司
Priority date: 2005-01-07
Filing date: 2005-12-13
Publication date: 2008-07-25

Description

Selected benzofuran derivatives

The present invention relates to novel 2, 4-diamino-5- (substituted) pyrimidines, pharmaceutical compositions containing them, processes for preparing them and their compositions, intermediates used in their synthesis, and their use in the treatment of bacterial infections.

Certain 2, 4-diamino-5-benzylpyrimidines have been shown to be potent inhibitors of dihydrofolate reductase (DHFR), which catalyzes the reduction of dihydrofolate to Tetrahydrofolate (THFA). This property has frequently shown to be a useful pharmaceutical property, particularly in the treatment of bacterial infections. U.K. patent specification No.875,562 thus describes, inter alia, 2, 4-diamino-5-benzylpyrimidines in which the benzyl residue is interrupted by three C' s_1-4Alkoxy substitution.

Trimethobenzaminopyrimidine, 2, 4-diamino-5- (3, 4, 5-trimethoxybenzyl grade) pyrimidine, is specifically disclosed in U.K. patent 875,562, and is the most effective antibacterial agent among the known 2, 4-diamino-5-benzylpyrimidines. Due to the mode of action of these benzyl pyrimidines, which enhance the antibacterial activity of sulfonamides, trimethoprim has been widely used in combination with various sulfonamides for human therapy during the last decade, in particular with sulfamethoxazole for the treatment of bacterial infections.

European patent applications 81109631.2 and 83104240.3 also disclose, inter alia, such compounds and their use.

WO02/10157 describes similar compounds. However, the compounds disclosed below show more potent anti-DHFR activity, including mutated enzymes, superior bioavailability, and superior antibacterial activity.

Thus, a group of novel benzofuran derivatives have been found to be more potent than trimethoprim and active against gram-positive pathogens (staphylococcus aureus, staphylococcus epidermidis, enterococcus faecalis or streptococcus pneumoniae) and gram-negative pathogens (haemophilus influenzae, escherichia coli, pneumobacillus, moraxella catarrhalis or proteus vulgaris). Furthermore, as described above, the compounds of formula I significantly exhibit improved activity against DHFR, including variant enzymes, superior bioavailability, and superior antibacterial activity.

The invention therefore relates to novel compounds of the general formula I,

wherein

R¹To represent

Wherein R is⁵Is cyano, carboxylic acid or

R⁹Represents hydrogen, lower alkoxy, lower alkylamino, lower alkyl containing 1 to 6 carbon atoms, aminocarbonylalkyl, mono-or dialkylaminoalkyl, alkoxyalkyl, aralkyl, aryl, heteroaryl, wherein the aryl or heteroaryl group is optionally mono-, di-or trisubstituted by straight-chain or branched lower alkyl of 1 to 4 carbon atoms, the substituents of which may be the same or different;

R¹⁰represents hydrogen or a C1-4 lower groupA lower alkyl group;

R⁹and R¹⁰Are connected through their nitrogen atoms to form a 3-, 4-, 5-or 6-membered heterocyclic ring, wherein the 5-or 6-membered ring optionally contains other oxygen, nitrogen or sulfur heteroatoms which may be the same or different, wherein the nitrogen may be substituted by lower alkyl, mono-or dialkylaminoalkyl or alkoxyalkyl groups having from 1 to 4 carbon atoms;

R⁶represents hydrogen, halogen, straight or branched chain lower alkyl or lower alkoxy containing 1 to 4 carbon atoms;

R⁷represents hydrogen or halogen;

R⁸represents hydrogen, a straight chain or branched lower alkyl group having 1 to 4 carbon atoms;

R²and R³Independently represents hydrogen, lower alkyl having 1 to 3 carbon atoms or bridges an oxygen atom with a lower alkylene having 1 to 3 carbon atoms to form a five-, six-or seven-membered ring;

R⁴represents hydrogen, lower alkyl having 1 to 4 carbon atoms;

and pharmaceutically acceptable salts thereof.

In the definition of the formula I, unless otherwise specified, the expression lower alkyl means a straight or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples of the lower alkyl group and the lower alkoxy group having 1 to 4 carbon atoms are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

The expression heteroaryl refers to a six-membered aromatic ring containing 1 to 4 nitrogen atoms; a benzo-six-membered aromatic ring containing 1 to 3 nitrogen atoms; a five-membered aromatic ring containing 1 oxygen atom, 1 nitrogen atom, or 1 sulfur atom; a benzo five-membered aromatic ring containing 1 oxygen atom, 1 nitrogen atom, or 1 sulfur atom; five-membered aromatic rings containing 1 oxygen atom and 1 nitrogen atom and benzo derivatives thereof; five-membered aromatic rings containing 1 sulfur atom and 1 nitrogen atom or 1 atom and benzo derivatives thereof; five-membered aromatic rings containing 2 nitrogen atoms and benzo derivatives thereof; five-membered aromatic rings containing 3 nitrogen atoms and benzo derivatives thereof, or tetrazole rings, for example, furyl, thienyl, pyrrolyl, pyridyl, indolyl, quinolyl, isoquinolyl, imidazolyl, triazinyl, thiazinyl, thiazolyl, isothiazolyl, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, and the like. Wherein the ring is optionally substituted with a lower alkyl group having 1 to 4 carbon atoms. The expression aryl represents an unsubstituted, mono-, di-or tri-substituted aromatic ring containing 6 to 10 carbon atoms, such as a phenyl or naphthyl ring, which may be optionally substituted with C1-C4 lower alkyl. The expression heterocycle denotes a saturated and unsaturated, but not aromatic, three-membered ring containing one heteroatom or a four-, five-or six-membered ring containing 1 to 2 heteroatoms of nitrogen, oxygen or sulfur, which may be the same or different. Examples are piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, dihydroimidazolyl, dihydropyrazolyl, pyrazolidinyl or dihydrooxazolyl, aziridine, azetidine. The expression halogen means fluorine, chlorine, bromine, and iodine, preferably fluorine, chlorine, and bromine.

A preferred group of compounds of the invention are compounds of the formula II

Wherein

R²And R³Represents a methyl group;

R⁴represents hydrogen;

R⁵、R⁶、R⁷and R⁸As defined in formula I.

Another preferred group of compounds of the invention are compounds of the formula III

Wherein

R²And R³Represents a methyl group;

R⁴represents hydrogen;

R⁵、R⁶、R⁷and R⁸As defined in formula I.

Another preferred group of compounds of the invention are compounds of the formula IV

Wherein

R²And R³Represents a methyl group;

R⁴represents hydrogen;

R⁵、R⁶、R⁷and R⁸As defined in formula I.

Another preferred group of compounds of the invention are compounds of the formula V

Wherein

R²And R³Represents a methyl group;

R⁴represents hydrogen;

R⁵、R⁶and R⁷As defined in formula I.

Another preferred group of compounds of the invention are compounds of the formula VI

Wherein

R²And R³Represents a methyl group;

R⁴represents hydrogen;

R⁵、R⁶and R⁷As defined in formula I.

Preferred compounds are those of the formulae I, II, III, IV, V and VI in which R is⁵Are carboxylic acid dimethylamide, carboxylic acid carboxamide, carboxylic acid diethylamide, carboxylic acid methoxamide, pyrrol-1-yl-methanone, morpholin-4-yl-methanone, carboxylic acid carboxamide, piperidin-1-yl-methanone, carboxylic acid N- (1, 3, 5-trimethyl-1H-pyrazol-4-yl) -amide, carboxylic acid N-methyl-benzyl-amide, 4- (2-methoxy-ethyl) -piperazine 1-yl-methanone, 4- (2-dimethylamino-ethyl) -piperazine 1-yl-methanone, carboxylic acid N- (2-dimethylamino-ethyl) -N-methyl-amide, carboxylic acid N-butyl-methyl-amide, carboxylic acid N-butyl-methyl, Carboxylic acid N-isopropyl-N-methyl-amide, carboxylic acid N-carbamoylmethyl-N-methyl-amide, carboxylic acid or cyano;

R⁶represents hydrogen, fluorine, chlorine or methoxy;

R⁷represents hydrogen, fluorine or chlorine;

R⁸represents hydrogen or methyl.

Particularly preferred compounds are selected from the group consisting of:

(4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -phenyl) -pyrrol-1-yl-methanone

4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N, N-diethyl-benzamide

(4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -phenyl) -piperidin-1-yl-methanone

4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N- (1, 3, 5-trimethyl-1H-pyrazol-4-yl) -benzamide

N-benzyl-4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N-methyl-benzamide

4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N, N-dimethyl-benzamide

5-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N, N-dimethyl-benzamide

4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -methyl-amino } -N, N-dimethyl-benzamide

4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -methyl-amino } -N-methyl-benzamide

2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -methyl-amino } -4-fluoro-N, N-dimethyl-benzamide

2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -5, N-trimethyl-benzamide

2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -6-fluoro-N, N-dimethyl-benzamide

2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N, N-dimethyl-benzamide

2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-fluoro-N, N-dimethyl-benzamide

3-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N, N-dimethyl-benzamide

3, 5-dichloro-2- [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethoxy ] -N, N-dimethyl-benzamide

4-chloro-2- [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethoxy ] -N-methyl-benzamide

2- [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethoxy ] -5-fluoro-N, N-dimethyl-benzamide

2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -3-methoxy-N, N-dimethyl-benzamide

2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -methyl-amino } -N, N-dimethyl-benzamide

3, 6-dichloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N, N-dimethyl-benzamide

4-chloro-2- [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethoxy ] -N, N-dimethyl-benzamide

(4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -phenyl) -morpholin-4-yl-methanone

N- (2-amino-5- {2- [ (5-chloro-2-cyano-phenylamine) -methyl ] -6, 7-dimethoxy-benzofuran-4-ylmethyl } -pyrimidin-4-yl) -isobutyramide

4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -benzonitrile

4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N-isopropyl-N-methyl-benzamide

N-butyl-4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N-methyl-benzamide

4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -benzoic acid

4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N- (2-dimethylamino-ethyl) -N-methyl-benzamide

(4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -phenyl) - [4- (2-dimethylamino-ethyl) -piperazin-1-yl ] -methanone

(4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -phenyl) - [4- (2-methoxy-ethyl) -piperazin-1-yl ] -methanone

N-Methylaminomethyl-4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N-methyl-benzamide

And pharmaceutically acceptable salts thereof.

The invention also relates to a method for preparing the compound of the general formula I

Wherein

R¹To represent

Wherein

R²、R³、R⁴、R⁵、R⁶、R⁷And R⁸As defined above for formula I, and,

the procedure comprises, as shown in scheme 1, reacting a compound of the general formula VII (cf. PCT journal WO02/10157) with an anhydride VIII, in which R is¹¹Represents a linear or branched lower alkyl group, giving a fully protected compound IX. The allyl group of compound IX is cleaved using tetrakis (triphenylphosphine) palladium as catalyst to give the compound of general formula X.

Scheme 1

Intermediates of the general formula X are novel compounds which serve as intermediates for the synthesis of active substances of the general formula I. Intermediate X (scheme 2) can be combined with the corresponding anthranilic acid derivative XI under acidic conditions, e.g., p-toluenesulfonic acid, to give compounds of formula XII, wherein R is¹As defined in formula I. Treatment of compound XII with excess aqueous sodium hydroxide affords the desired compound of formula I.

Scheme 2

Synthesis of some unknown anthranilic acid derivatives of formula XI,

wherein R is⁵To represent

And R is⁶、R⁷、R⁸、R⁹And R¹⁰As defined above for formula I, XIII can be prepared by reacting anthranilic acid (when R is⁸Representing lower alkyl, can be reacted with the corresponding aldehyde, obtained by reductive amination using general procedure C (comparative experimental section) with amine XIV using standard peptide coupling reagents such as N-ethyl-N '(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 1-Hydroxybenzotriazole (HOBT) or O- (benzotriazol-1-yl) -N, N' -tetramethyluronium tetrafluoroborate (TBTU), as described in scheme 3. The resulting anthranilic acid derivative XI was combined with compound X using the procedure described in scheme 2 to give the compound of formula I.

Scheme 3

Another group of substituents can be obtained by the reaction according to scheme 4.

Scheme 4

The intermediates of the general formula XVI are novel compounds which serve as intermediates for the synthesis of the active substances of the general formula I. The alcohol X is activated by reaction with a sulfonyl chloride compound of the formula XV, wherein R¹²Represents lower alkyl or aryl to give intermediate XVI. The compound XVI obtained is reacted with anthranilic acid derivatives XI using Lewis acids, e.g. ZnCl₂The reaction gives the compound XII. As shown in scheme 4, further treatment with alkali gives compounds of the formula IA compound is provided.

Another group of substituents can be obtained by the reaction according to scheme 5.

The intermediates of the general formula XVII are novel compounds which serve as intermediates for the synthesis of the active substances of the general formula I. Alcohol X is oxidized using excess manganese dioxide to give aldehyde XVII. The compound XVII obtained is reacted with anthranilic acid derivative XI under reductive amination conditions. Schiff's base is formed under acidic conditions, or triethyl orthoformate (triethylohormomat) is added as a dehydrating agent and then reduced with sodium borohydride to give the compound of formula XII. Final treatment with base as depicted in scheme 5 affords compounds of formula I.

Scheme 5

The compounds of formula I can be synthesized using another procedure. Compound XVII with aniline XVIII, wherein R⁵As defined in formula I, under reductive amination conditions. Under strongly acidic conditions, e.g., trifluoroacetic acid, a schiff base is formed, as shown in scheme 6, and then reduced using sodium triacetoxyborohydride to give a mixture of XIX. At R⁵In the specific case of carboxylic acids, the coupling with the corresponding amine XIV is carried out using standard amide coupling procedures, O- (benzotriazol-1-yl) -N, N' -tetramethyluronium tetrafluoroborate (TBTU) as coupling reagent. Final treatment with base as depicted in scheme 6 gives compounds of formula I.

Scheme 6

Wherein

R¹To represent

Wherein

which comprises the step of reacting a compound of the general formula XX (see PCT publication WO02/10157) with the corresponding anthranilic acid derivative or phenol XXI, wherein Z represents NHR, under basic conditions, as shown in scheme 7⁸Or OH.

Scheme 7

Test section

Abbreviations:

ACN: acetonitrile

ATCC: american type culture Collection

CH₂Cl₂: methylene dichloride

DMF: dimethyl formamide

DMSO, DMSO: dimethyl sulfoxide

EDC: N-Ethyl-N' (3-dimethylaminopropyl) carbodiimide hydrochloride

Eq.: equivalent weight

ESI: electrospray ionization mass spectrometry

EtOH: ethanol

FC: chromatographic purification

HOBT: 1-hydroxybenzotriazoles

HPLC: high performance liquid chromatography

KHSO₄: potassium hydrogen sulfate

MeOH: methanol

MgSO₄: magnesium sulfate

MS: mass spectrometric analysis

NMR: nuclear magnetic resonance

p-TosOH: p-toluenesulfonic acid

TFA: trifluoroacetic acid

THF: tetrahydrofuran (THF)

TLC: thin layer chromatography

TBTU: o- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate

General procedure a: protecting the diamine pyrimidinyl radical (scheme 1)

Compound VII (1eq.) was suspended in anhydride VIII (2.5eq.) under argon at room temperature. The suspension was stirred and heated at 150 ℃ until a clear solution was obtained. After the reaction was complete (6 hours), ethyl acetate was added, water and NaHCO₃The organic layer was washed with brine, MgSO₄And drying. Evaporation of the solvent under reduced pressure gave compound IX, which was used without further purification.

Example 1:

according to general procedure a, N- [5- (2-allyloxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -4- (2, 2-dimethyl-propionylamino) -pyrimidin-2-yl ] -2, 2-dimethyl-propionamide (quantitative yield from HPLC-MS curve) was obtained as a brown oil by reacting (5- (2-allyloxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidine-2, 4-diamine) (1eq., 5g, 13.5mmol) with pivalic acid anhydride (2.5eq., 7.0mL, 34.5 mmol).

MS ESI：539.2[M+H]⁺

General procedure B: allyl cleavage (scheme 1)

To a solution of compound IX (1eq.) in ACN was added tetrakis (triphenylphosphine) palladium (0.25eq.) and ammonium formate (5eq.) under argon. The resulting mixture was heated at 80 ℃ until the reaction was complete. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, over MgSO₄Dried above and the solvent evaporated under reduced pressure. After purification by FC (cyclohexane: EtOAc) compound X is obtained.

Example 2:

according to general procedure B, N- [4- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-2-yl ] -2, 2-dimethyl-propionamide (5g, 9.29mmol, 1eq.), tetrakis (triphenylphosphine) palladium (2.68g, 2.32mmol, 0.25eq.) and ammonium formate (2.93g, 46.46mmol, 5eq.) are reacted to give N- [4- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-2-yl ] -2, 2-dimethyl-propionamide (quantitative yield from HPLC-MS curves).

MS ESI：499.2[M+H]⁺。

Example 3:

the isobutyric anhydride was used according to general procedure A to give N- [5- (2-allyloxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -2-isobutyrylamino-pyrimidin-4-yl ] -isobutyramide and the allyl group was cleaved according to general procedure B to give N- [5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -2-isobutyrylamino-pyrimidin-4-yl ] -isobutyramide, which was used in the next step without further purification.

MS ESI：471.0[M+H]⁺

General procedure C: methylation of anthranilic acid derivatives

To anthranilic acid derivative XI (where R is R) under argon at room temperature⁸Hydrogen, 1eq.) to a solution of ACN was added sodium cyanoborohydride (3.5eq.) and formaldehyde (1.3 eq.). After stirring for 5 minutes, the reaction mixture was adjusted to pH 3 using 1N HCl solution. After completion of the reaction, the mixture was diluted with dichloromethane and saturated NaHCO₃The organic layer was washed with the solution and brine. Over MgSO₄Drying above and evaporating the solvent under reduced pressure to give Compound XI (wherein R is⁸Is methyl) which was used without further purification.

Example 4:

according to general procedure C, 4-fluoro-2-methylamino-benzoic acid (830mg, 76%) was obtained by reacting 2-amino-4-fluoro-benzoic acid (1g, 6.44mmol), sodium cyanoborohydride (1.62g, 25.76mmol) and formaldehyde (667 μ L, 8.37 mmol).

MS ESI：170.1[M+H]⁺

Example 5:

according to general procedure C, 4-chloro-2-methylamino-benzoic acid (1.61g, 75%) was obtained by reacting 4-chloro-2-amino-benzoic acid (2g, 11.66mmol), sodium cyanoborohydride (2.93g, 46.64mmol) and formaldehyde (1.21mL, 15.16 mmol).

MS ESI：186.0[M+H]⁺

General procedure D: preparation of amides (scheme 3)

To compound XIII (1eq.) in DMF was added amine XIV (5eq.) at room temperature under argon. 1-hydroxybenzotriazole hydrate (1.2eq.), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (1.2eq.), triethylamine (1 to 3eq.) if necessary, were added. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and 0.1M KHSO₄Solution, saturated NaHCO₃Washing with solution, water, and brineThe organic layer was washed. Over MgSO₄Drying above and evaporation of the solvent under reduced pressure gave compound XI, which was used without further purification.

Example 6

Following general scheme D, by reacting 2-amino-4-chloro-benzoic acid (1g, 5.82mmol), pyrrolidine (57 μ L, 6.99mmol), 1-hydroxybenzotriazole hydrate (945mg, 6.99mmol), and (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (1.34g, 6.99mmol), we obtained (2-amino-4-chloro-phenyl) -pyrrolidin-1-yl-methanone (1.37g, 99%)

MS ESI：225[M+H]⁺

Example 7:

following general scheme D, 2-amino-4-chloro-N, N-diethyl-benzamide (1.25g, 95%) was obtained by reacting 2-amino-4-chloro-benzoic acid (1g, 5.82mmol), diethylamine (369 μ L, 6.99mmol), 1-hydroxybenzotriazole hydrate (945mg, 6.99mmol), and (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (1.34g, 6.99mmol).

MS ESI：227[M+H]⁺

Example 8:

according to general procedure D, 2-amino-4-chloro-N- (1, 3, 5-trimethyl-1H-pyrazol-4-yl) -benzamide (164mg, 72%) was obtained by reacting 2-amino-4-chloro-benzoic acid (140mg, 0.79mmol), 1, 3, 5-trimethyl-1H-pyrazol-4-ylamine (500mg, 3.99mmol), 1-hydroxybenzotriazole hydrate (130mg, 0.96mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (183mg, 0.96mmol), and triethylamine (220. mu.L, 1.60 mmol).

MS ESI：279[M+H]⁺

Example 9:

according to general procedure D, 2-amino-4-fluoro-N, N-dimethyl-benzamide (quantitative yield from HPLC-MS curves) was obtained by reacting 2-amino-4-fluoro-benzoic acid (1g, 6.44mmol), dimethylamine hydrochloride (630mg, 7.73mmol), 1-hydroxybenzotriazole hydrate (1.04g, 7.73mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (1.48g, 7.73mmol), and triethylamine (2.68mL, 19.3 mmol).

MS ESI：183.1[M+H]⁺

Example 10:

following general procedure D, 2-amino-4-chloro-N, N-dimethyl-benzamide (10.36g, 89%) was obtained by reacting 2-amino-4-chloro-benzoic acid (10g, 58.3mmol), dimethylamine hydrochloride (5.71g, 70.0mmol), 1-hydroxybenzotriazole hydrate (9.45g, 70.0mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (13.41g, 70.0mmol), and triethylamine (24.3mL, 70.0 mmol).

MS ESI：199.0[M+H]⁺

Example 11:

following general procedure D, 2-amino-6-fluoro-N, N-dimethyl-benzamide (1.78g, 76%) was obtained by reacting 2-amino-6-fluoro-benzoic acid (2g, 12.9mmol), dimethylamine hydrochloride (1.26g, 15.9mmol), 1-hydroxybenzotriazole hydrate (2.09g, 15.5mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (2.97g, 15.5mmol), and triethylamine (9.4mL, 38.7 mmol).

MS ESI：183.1[M+H]⁺

Example 12:

according to general procedure D, 4-fluoro-N, N-dimethyl-2-methylamino-benzamide (quantitative yield from HPLC-MS curves) was obtained by reacting 4-fluoro-2-methylamino-benzoic acid (410mg, 2.43mmol), dimethylamine hydrochloride (238mg, 2.92mmol), 1-hydroxybenzotriazole hydrate (395mg, 2.92mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (560mg, 2.92mmol), and triethylamine (1.01mL, 7.29 mmol).

MS ESI：197.0[M+H]⁺

Example 13:

following general procedure D, 5-chloro-N, N-dimethyl-2-methylamino-benzamide (610mg, 71%) was obtained by reacting 5-chloro-2-methylamino-benzoic acid (750mg, 4.05mmol), dimethylamine hydrochloride (396mg, 4.86mmol), 1-hydroxybenzotriazole hydrate (656mg, 4.86mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (931mg, 4.86mmol) and triethylamine (1.7mL, 12.15 mmol).

MS ESI：213.0[M+H]⁺

Example 14:

following general procedure D, 4-chloro-N, N-dimethyl-2-methylamino-benzamide (859mg, 99%) was obtained by reacting 4-chloro-2-methylamino-benzoic acid (750mg, 4.05mmol), dimethylamine hydrochloride (396mg, 4.86mmol), 1-hydroxybenzotriazole hydrate (656mg, 4.86mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (931mg, 4.86mmol), and triethylamine (1.7mL, 12.15 mmol).

MS ESI：213.0[M+H]⁺

Example 15:

following general procedure D, 2-chloro-N, N-dimethyl-6-methylamino-benzamide (309mg, 43%) was obtained by reacting 2-chloro-6-methylamino-benzoic acid (630mg, 3.41mmol), dimethylamine hydrochloride (334mg, 4.09mmol), 1-hydroxybenzotriazole hydrate (552mg, 4.09mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (781mg, 4.09mmol), and triethylamine (1.12mL, 10.23 mmol).

MS ESI：213.0[M+H]⁺

Example 16:

following general procedure D, 2-amino-3-chloro-N, N-dimethyl-benzamide (750mg, 65%) was obtained by reacting 2-amino-3-chloro-benzoic acid (1g, 5.83mmol), dimethylamine hydrochloride (571mg, 7.00mmol), 1-hydroxybenzotriazole hydrate (945mg, 7.00mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (1.34g, 7.00mmol), and triethylamine (2.43mL, 17.49 mmol).

MS ESI：199.0[M+H]⁺

Example 17:

following general procedure D, 4-chloro-2-hydroxy-N, N-dimethyl-benzamide (1.82g, 78%) was obtained by reacting 4-chloro-2-hydroxy-benzoic acid (2g, 11.60mmol), dimethylamine hydrochloride (1.14g, 19.92mmol), 1-hydroxybenzotriazole hydrate (1.87g, 13.92mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (2.66g, 13.92mmol), and triethylamine (4.84mL, 34.80 mmol).

MS ESI：200.1[M+H]⁺

Example 18:

following general procedure D, 5-fluoro-2-hydroxy-N, N-dimethyl-benzamide (1.02g, 43%) was obtained by reacting 5-fluoro-2-hydroxy-benzoic acid (2g, 12.8mmol), dimethylamine hydrochloride (1.25g, 15.36mmol), 1-hydroxybenzotriazole hydrate (2.07g, 15.36mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (2.94g, 15.36mmol) and triethylamine (4.88mL, 38.78 mmol).

MS ESI：184.0[M+H]⁺

Example 19:

according to general procedure D, (2-amino-4-chloro-phenyl) -morpholin-4-yl-methanone (quantitative yield from HPLC-MS curve) is obtained by reaction of 2-amino-4-chloro-benzoic acid (100mg, 0.58mmol), morpholine (61. mu.l, 0.70mmol), 1-hydroxybenzotriazole hydrate (95mg, 0.70mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (134mg, 0.70mmol) and triethylamine (161. mu.l, 1.16 mmol).

MS ESI：241.1[M+H]⁺

General procedure E: preparation of amides Using TBTU

To a solution of anthranilic acid XIII (1eq.) in DMF at room temperature under argon was added continuously amine XIV (5eq.), O- (benzotriazol-1-yl) -N, N' -tetramethyluronium tetrafluoroborate (1-5 eq.), and if necessary triethylamine (2eq.) to. After completion of the reaction, the mixture was diluted with ethyl acetate and saturated NaHCO₃The organic layer was washed with solution, water and brine. Over MgSO₄The organic phase obtained is dried and evaporated under reduced pressure to give the corresponding amide XI, which is used without further purification.

Example 20:

following general procedure E, 2-amino-N-benzyl-4-chloro-N-methyl-benzamide (1.52g, 95%) was obtained by reaction of 2-amino-4-chloro-benzoic acid (1g, 5.83mmol), benzyl-methyl-amine (3.75mL, 29.1mmol), O- (benzotriazol-1-yl) -N, N' -tetramethyluronium tetrafluoroborate (2.2g, 6.86 mmol).

MS ESI：275.1[M+H]⁺

Example 21:

following general procedure E, 2-amino-N-carbamoylmethyl-4-chloro-N-methyl-benzamide (545mg, 77%) was obtained by reacting 2-amino-4-chloro-benzoic acid (500mg, 2.91mmol), 2-methylamino-acetamide hydrochloride (362mg, 2.91mmol), O- (benzotriazol-1-yl) -N, N' -tetramethyluronium tetrafluoroborate (1.86g, 5.82mmol) and triethylamine (810 μ L, 5.82 mmol).

MS ESI：241.9[M+H]⁺

Example 22:

following general procedure E, 2-amino-4-chloro-N-isopropyl-N-methyl-benzamide (quantitative yield from HPLC-MS curve) was obtained by reaction of 2-amino-3, 5-dichloro-benzoic acid (10g, 58.41mmol), isopropyl-methyl-amine (30mL, 292.0mmol), O- (benzotriazol-1-yl) -N, N' -tetramethyluronium tetrafluoroborate (22.5g, 70.09 mmol).

MS ESI：227.1[M+H]⁺

General procedure F: coupling procedure Using p-toluenesulfonic acid (scheme 2)

P-toluenesulfonic acid (2.5eq.) and anthranilic acid derivative XI (1eq.) were added to a solution of X (1-1.2 eq.) in acetonitrile at room temperature under argon. The reaction mixture was stirred and heated at 70 ℃ until the reaction was complete. With saturated NaHCO₃The reaction mixture was quenched with solution and extracted with dichloromethane. The organic layer was washed with water, saturated NaCl solution, over MgSO₄Dried and evaporated under reduced pressure. The resulting compound XII (1eq.) is dissolved in methanol or isopropanol and an excess of 4N NaOH solution (10eq.) is added. The resulting mixture was heated at 50 ℃ until the reaction was complete. The reaction was quenched with water and extracted with dichloromethane. With saturated NaHCO₃The organic layer was washed with water, brine, MgSO₄Dried and evaporated under reduced pressure. Purification by FC, CH₂Cl₂～CH₂Cl₂Gradient elution with/methanol (9/1) afforded Compound I.

Example 23:

according to general procedure F, (4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-4-ylmethyl ] -pyrimidin-4-yl ] -amino } -was obtained by reacting N- [2- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl) -6, 7-dimethoxy-benzofuran-4-ylmethyl ] -pyrimidin-4-yl- ] -2, 2-dimethyl-propionamide (200mg, 0.40mmol), p-toluenesulfonic acid (159mg, 0.83mmol), (2-amino-4-chloro-phenyl) -pyrrol-1-yl-methanone (75mg, 0.33mmol), and 4NNaOH (293. mu.L, 1.17mmol) -phenyl) -pyrrol-1-yl-methanone (41mg, 19%).

MS ESI：539.0[M+H]⁺

Example 24:

according to general procedure F, 4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-4-ylmethyl ] -pyrimidin-4-yl ] -amino } -N was obtained by reacting N- [2- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide (200mg, 0.40mmol), p-toluenesulfonic acid (159mg, 0.83mmol), 2-amino-4-chloro-N, N-diethyl-benzamide (76mg, 0.33mmol), and 4N NaOH (335. mu.L, 1.34mmol), n-diethyl-benzamide (45mg, 21%).

MS ESI：537.0[M+H]⁺

Example 25:

according to general procedure F, (4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-4-ylmethyl ] -amino } -benzene was obtained by reacting N- [2- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide (200mg, 0.40mmol), p-toluenesulfonic acid (159mg, 0.83mmol), (2-amino-4-chloro-phenyl) -piperidin-1-yl-methanone (80mg, 0.33mmol), and 4N NaOH (267. mu.L, 1.06mmol) Yl) -piperidin-1-yl-methanone (38mg, 17%).

MS ESI：551.0[M+H]⁺

Example 26:

according to general procedure F, 4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6 is obtained by reacting N- [2- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide (200mg, 0.40mmol), p-toluenesulfonic acid (191mg, 1.00mmol) and 2-amino-4-chloro-N- (1, 3, 5-trimethyl-1H-pyrazol-4-yl) -benzamide (113mg, 0.40mmol) and 4N NaOH (524. mu.L, 2.09mmol), 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N- (1, 3, 5-trimethyl-1H-pyrazol-4-yl) -benzamide (17mg, 7%).

MS ESI：590.9[M+H]⁺

Example 27:

according to general procedure F, N- [2- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide (200mg, 0.40mmol), p-toluenesulfonic acid (191mg, 1.00mmol), 2-amino-N-benzyl-4-chloro-N-methyl-benzamide (150mg, 0.40mmol), and 4N NaOH (757. mu.L, 3.03mmol) are reacted to give N-benzyl-4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N-methyl-benzamide (60mg, 25%).

MS ESI：586.9[M+H]⁺

General procedure G: coupling of anthranilic acid derivatives with Zinc chloride (scheme 4)

To a solution of X (1eq.) in dichloromethane was added sulfonyl chloride XV, such as methanesulfonyl chloride (1.2eq.) and triethylamine (1.2eq.) at 0 ℃ under argon. The resulting mixture was stirred at room temperature until the reaction was complete. The reaction was then quenched with water and the layers separated. The organic phase containing Compound XVI is reacted over MgSO₄Dried and used for the next step of synthesis.

To a solution of anthranilic acid derivative XI (1.2eq.) in dichloromethane was added zinc chloride (1.2eq.) at room temperature under argon. After stirring for 10 minutes, a solution of prepared XVI (1eq.) in dichloromethane was added. After the reaction was complete, saturated NaHCO was used₃The mixture was quenched with solution and extracted twice with dichloromethane. The organic layer was washed with water, brine, over MgSO₄Drying above and evaporation under reduced pressure gave compound XII, which was used without further purification.

The resulting compound XII (1eq.) is dissolved in methanol or isopropanol and an excess of 4N NaOH solution (10eq.) is added. The resulting mixture was heated at 50 ℃ until the reaction was complete. The reaction was quenched with water and extracted with dichloromethane. With saturated NaHCO₃The organic layer was washed with water, brine, MgSO₄Dried above and evaporated under reduced pressure. Purification by FC, CH₂Cl₂～CH₂Cl₂Gradient elution with/methanol (9/1) afforded Compound I.

Example 28:

according to general procedure G, 4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6 is obtained by reacting N- [2- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide (2.57G, 5.15mmol), methanesulfonyl chloride (480. mu.L, 6.18mmol), triethylamine (861. mu.L, 6.18mmol), zinc chloride (840mg, 6.18mmol), 2-amino-4-chloro-N, N-dimethyl-benzamide (1.23G, 6.18mmol), and 4N NaOH (2.42mL, 9.68mmol), 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N, N-dimethyl-benzamide (2g, 76%).

MS ESI：511.2[M+H]⁺

Example 29:

according to general procedure G, 5-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6 is obtained by reacting N- [2- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide (300mg, 0.60mmol), methanesulfonyl chloride (60. mu.L, 0.72mmol), triethylamine (100. mu.L, 0.72mmol), zinc chloride (83mg, 0.61mmol), 2-amino-5-chloro-N, N-dimethyl-benzamide (121mg, 0.61mmol), and 4N NaOH (309. mu.L, 1.23mmol), 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N, N-dimethyl-benzamide (77mg, 25%).

MS ESI：511.0[M+H]⁺

Example 30:

according to general procedure G, 4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6 was obtained by reacting N- [2- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide (250mg, 0.50mmol), methanesulfonylchloride (47. mu.L, 0.60mmol), triethylamine (84. mu.L, 0.60mmol), zinc chloride (71mg, 0.52mmol), 4-chloro-N, N-dimethyl-2-methylamino-benzamide (110mg, 0.52mmol) and 4N NaOH (267. mu.L, 1.06mmol), 7-dimethoxy-benzofuran-2-ylmethyl ] -methyl-amino } -N, N-dimethyl-benzamide (56mg, 21%).

MS ESI：524.9[M+H]⁺

Example 31:

according to general procedure G, 4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6 was obtained by reacting N- [2- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide (300mg, 0.60mmol), methanesulfonyl chloride (56. mu.L, 0.72mmol), triethylamine (100. mu.L, 0.72mmol), zinc chloride (98mg, 0.72mmol), 4-chloro-N-methyl-2-methylamino-benzamide (143mg, 0.72mmol), and 4N NaOH (318. mu.L, 1.27mmol), 7-dimethoxy-benzofuran-2-ylmethyl ] -methyl-amino } -N-methyl-benzamide (52mg, 17%).

MS ESI：510.9[M+H]⁺

Example 32:

according to general procedure G, by reacting N- [2- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide (250mg, 0.50mmol), methanesulfonyl chloride (47. mu.L, 0.60mmol), triethylamine (84. mu.L, 0.60mmol), zinc chloride (71mg, 0.52mmol), 4-chloro-N, N-dimethyl-2-methylamino-benzamide (102mg, 0.52mmol), and 4N NaOH (236. mu.L, 0.94mmol), 2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6 is obtained, 7-dimethoxy-benzofuran-2-ylmethyl ] -methyl-amino } -4-fluoro-N, N-dimethyl-benzamide (40mg, 15%).

MS ESI：508.9[M+H]⁺

Example 33:

according to general procedure G, by reacting N- [2- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide (280mg, 0.40mmol), methanesulfonyl chloride (38. mu.L, 0.48mmol), triethylamine (67. mu.L, 0.48mmol), zinc chloride (64mg, 0.47mmol), 2-amino-5, N, N-trimethyl-benzamide (70mg, 0.39mmol), and 4N NaOH (641. mu.L, 2.56mmol), 2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6 is obtained, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -5, N, N-trimethyl-benzamide (13mg, 6.6%).

MS ESI：490.9[M+H]⁺

Example 34:

according to general procedure G, by reacting N- [2- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide (287mg, 0.40mmol), methanesulfonyl chloride (31. mu.L, 0.40mmol), triethylamine (56. mu.L, 0.40mmol), zinc chloride (66mg, 0.40mmol), 2-amino-6-fluoro-N, N-dimethyl-benzamide (74mg, 0.40mmol) and 4N NaOH (593. mu.L, 2.37mmol) 2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6 is obtained, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -6-fluoro-N, N-dimethyl-benzamide (22mg, 11%).

MS ESI：495.1[M+H]⁺

Example 35:

according to general procedure G, 2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } - N, N-dimethyl-benzamide (55mg, 23%).

MS ESI：477.0[M+H]⁺

Example 36:

according to general procedure G, by reacting N- [2- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide (300mg, 0.60mmol), methanesulfonyl chloride (60. mu.L, 0.72mmol), triethylamine (100. mu.L, 0.72mmol), zinc chloride (83mg, 0.61mmol), (109mg, 0.61mmol), 2-amino-N, N-dimethyl-benzamide (109mg, 0.61mmol) and 4N NaOH (286. mu.L, 1.14mmol) 2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6 is obtained, 7-dimethoxy-benzofuran-2-ylmethyl ] -methyl-amino } -N, N-dimethyl-benzamide (68mg, 23%).

MS ESI：491.0[M+H]⁺

Example 37:

according to general procedure G, by reacting N- [2- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide (280mg, 0.40mmol), methanesulfonyl chloride (37. mu.L, 0.48mmol), triethylamine (67. mu.L, 0.48mmol), zinc chloride (64mg, 0.47mmol), 2-amino-3-methoxy-N, N-dimethyl-benzamide (76mg, 0.40mmol), and 4N NaOH (666. mu.L, 1.92mmol) 2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6 is obtained, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -3-methoxy-N, N-dimethyl-benzamide (25.8mg, 13%).

MS ESI：507.1[M+H]⁺

General procedure H: oxidation of alcohols to aldehydes (scheme 5)

Manganese dioxide (10eq.) was added to a solution of compound X (1eq.) in dichloromethane at room temperature under argon. The suspension was stirred under argon until the reaction was complete. The resulting reaction mixture was filtered through celite over MgSO₄Dried above and the solvent evaporated under reduced pressure. Purification by FC, cyclohexane-gradient elution of cyclohexane/EtOAc (1/2) afforded Compound XVII.

Example 38:

according to general procedure H, N- [2- (2, 2-dimethyl-propionylamino) -5- (2-hydroxymethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide (2.85g, 5.73mmol) and manganese dioxide (5.0g, 57.37mmol) are reacted to give N- [2- (2, 2-dimethyl-propionylamino) -5- (2-formyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide as a yellow solid (650mg, 27%).

MS ESI：497.1[M+H]⁺

Example 39:

according to general procedure H, N- [5- (2-formyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -2-isobutyramido-pyrimidin-4-yl ] -isobutyramide was prepared and used in the next step without further purification.

MS ESI：469.0[M+H]⁺

General procedure I: reductive amination Using p-toluenesulfonic acid (p-TosOH) (scheme 5)

To a toluene solution of compound XVII (1eq.) and anthranilic acid derivative XI (1eq.) was added p-toluenesulfonic acid (0.2eq.) under argon at room temperature. The resulting mixture was heated at 110 ℃ for 5 days. Sodium borohydride (2eq.) was added and the mixture was stirred at room temperature. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane and saturated NaHCO₃The organic layer was washed with brine. Over MgSO₄Drying above and evaporating the solvent under reduced pressure gives compound XII. The resulting compound XII (1eq.) is dissolved in methanol or isopropanol and an excess of 4N NaOH solution (10eq.) is added. The resulting mixture was heated at 50 ℃ until the reaction was complete. The reaction was quenched with water and extracted with dichloromethane. With saturated NaHCO₃The organic layer was washed with water, brine, MgSO₄Dried above and evaporated under reduced pressure. Purification by FC, CH₂Cl₂～CH₂Cl₂Gradient elution with/methanol (9/1) afforded Compound I.

Example 40:

by reacting N- [2- (2, 2-dimethyl-propionylamino) -5- (2-formyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-4-yl ] -2, 2-dimethyl-propionamide (50mg, 0.1mmol), 2-amino-4-chloro-N, N-dimethyl-benzamide (20mg, 0.1mmol), p-toluenesulfonic acid (4mg, 0.02mmol), and sodium boron hydride (8mg, 0.2mmol) according to general procedure I, 4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N is obtained, n-dimethyl-benzamide (18mg, 35%).

MS ESI：510.1[M+H]⁺

General procedure J: reductive amination Using TFA (scheme 6)

Aniline XVIII (1eq.) and trifluoroacetic acid (2-6eq.) were added to a freshly distilled THF solution of compound XVII (1eq.) at room temperature under argon. The resulting mixture was stirred and heated at 50 ℃ for 3 hours. Then cooled to-10 ℃ and sodium triacetoxyborohydride (2-3eq.) was added. The reaction mixture was stirred at room temperature until the reaction was complete. The mixture was diluted with ethyl acetate and saturated NaHCO₃The organic layer was washed with the solution over MgSO₄Dried above and evaporated under reduced pressure. The resulting intermediate was used in the next step without further purification.

Example 41:

according to general procedure J, N- [5- (2-formyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -2-isobutyrylamino-pyrimidin-4-yl ] -isobutyramide (1g, 2.13mmol), 2-amino-4-chloro-benzoic acid (366mg, 2.13mmol), trifluoroacetic acid (327. mu.L, 4.27mmol), and sodium triacetoxyborohydride (1.35g, 6.40mmol) reacted to give a mixture containing 2- { [4- (2, 4-bis-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-benzoic acid and 2- { [4- (2-amino-4-isobutyrylamino- Pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-benzoic acid (ratio 1: 2) (quantitative yield from HPLC-MS curves) in a mixture XIX (cf. scheme 6). This mixture was used in general step O without further purification.

MS ESI：624.3[M+H]⁺

MS ESI：554.2[M+H]⁺

Example 42:

according to general procedure J, 2- { [4- (2-amino-4-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-N-isopropyl-N-methyl-benzamide (2.4g, 10.68mmol), trifluoroacetic acid (2.45mL, 32.04mmol), sodium triacetoxyborohydride (6.79g, 32.04mmol) was reacted by N- [5- (2-formyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -2-isobutyrylamino-pyrimidin-4-yl ] -isobutyramide (5g, 10.68mmol) to give 2- { [4- (2-amino-4-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-N-isopropyl-N-methyl Benzamide (3.6g, 55%).

MS ESI：609.0[M+H]⁺

Example 43:

according to general procedure J, N- [5- (2-formyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -2-isobutyrylamino-pyrimidin-4-yl ] -isobutyramide (100mg, 0.21mmol), 2-amino-4-chloro-cyanobenzene (33mg, 0.21mmol), trifluoroacetic acid (33. mu.L, 0.42mmol), sodium triacetoxyborohydride (90mg, 0.42mmol) reacted to give N- (4-amino-5- {2- [ (5-chloro-2-cyano-phenylamine) -methyl ] -6, 7-dimethoxy-benzofuran-4-ylmethyl } -pyrimidin-2-yl) -isobutyramide (quantitative yield from HPLC-MS curve).

MS ESI：535[M+H]⁺

Example 44:

according to general procedure J, N- [ 4-amino-5- (2- { [ 5-chloro-2- (morpholine-4-carbonyl) -phenylamino ] -methyl } -6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-2-yl ] -N- [ 4-amino-5- (2- { [ 5-chloro-2- (morpholine-4-carbonyl) -phenylamino ] -6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-2-yl ] -was obtained by reacting N- [5- (2-formyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -4-isobutyrylamino-pyrimidin-2-yl ] -isobutyramide (100mg, 0.21mmol), (2-amino-4-chloro-phenyl) -morpholin-4-yl-methanone (51mg, 0.21mmol), trifluoroacetic acid (98. mu.L, 1.28mmol), sodium triacetoxyborohydride (135mg, 0.64mmol) Isobutyramide (quantitative yield from HPLC-MS curve).

MS ESI：623.0[M+H]⁺

General procedure K: deprotection of diaminopyrimidine (scheme 6)

The compound obtained in general step J (1eq.) was dissolved in methanol or isopropanol and an excess of 4n naoh solution (4-10eq.) was added. The resulting mixture was heated at 50 ℃. After completion of the reaction, the reaction was quenched with water and extracted with dichloromethane. With saturated NaHCO₃The organic layer was washed with water, brine, and then washed with MgS0₄Dried above and evaporated under reduced pressure. Purification by FC, CH₂Cl₂～CH₂Cl₂Gradient elution with/methanol (9/1) afforded Compound I.

Example 45:

according to general procedure K, 4-chloro-2- { [4- (2, 4-bis-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-benzoic acid was obtained by reacting a mixture XIX (cf. scheme 6, described in general procedure J, 100mg, 0.16mmol) of 2- { [4- (2-amino-4-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-benzoic acid (ratio 1: 2) with 4N NaOH (400. mu.L, 1.6mmol) to give 4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -benzoic acid (10mg, 13%).

MS ESI：484.3[M+H]⁺

Example 46:

by reacting 2- { [4- (2-amino-4-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-N-isopropyl-N-methyl-benzamide (3.6g, 5.9mmol) and 4N NaOH (5.34mL, 21.36mmol) according to general procedure K, 4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N-isopropyl-N-methyl-benzamide (908mg, 28.5%).

MS ESI：539.0[M+H]⁺

Example 47:

4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -benzonitrile (24mg, 25%) was prepared by reacting N- [ 4-amino-5- (2- { [ 5-chloro-2-cyano-phenylamino ] -methyl } -6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-2-yl ] -isobutyramide (128mg, 0.21mmol) and NaOH 4N (213mL, 0.85mmol) according to general procedure K.

MS ESI：465.0[M+H]⁺

Example 48:

by reacting N- [ 4-amino-5- (2- { [ 5-chloro-2- (morpholine-4-carbonyl) -phenylamino ] -methyl } -6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidin-2-yl ] -isobutyramide (213mg, 0.34mmol) with NaOH 4N (342. mu.L, 1.37mmol) according to general procedure K, 4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -phenyl-morpholin-4-yl-methanone (47mg, 25%).

MS ESI：553.1[M+H]⁺

General procedure L: preparation and deprotection of amides (scheme 6)

To a suspension of mixture XIX (1eq.) of general step J above in dichloromethane was added 1-hydroxybenzotriazole hydrate (1.2eq), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (1.2eq) and amine XIV (1.2eq) at room temperature under argon. The resulting mixture was stirred at 40 ℃ until the reaction was complete. The mixture was diluted with dichloromethane and saturated NaHCO₃And a brine wash. Over MgSO₄Drying above and evaporating the solvent under reduced pressure to give the compound. The resulting compound (1eq.) was dissolved in methanol or isopropanol and an excess of 4N NaOH solution (6 eq) was added.). The mixture was heated at 50 ℃ overnight, or in a microwave at 110 ℃ for 10 minutes. After completion of the reaction, the reaction was quenched with water and extracted with dichloromethane. With saturated NaHCO₃The organic layer was washed with water, brine, MgSO₄Dried above and evaporated under reduced pressure. Purification by FC, CH₂Cl₂～CH₂Cl₂Gradient elution with/methanol (9/1) afforded Compound I.

Example 49:

according to general procedure L, the starting material was purified by reaction of a mixture XIX (cf. scheme 6) containing 2- { [4- (2, 4-bis-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-benzoic acid and 2- { [4- (2-amino-4-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-benzoic acid (ratio 1: 2) (200mg, 0.32mmol), 1-hydroxybenzotriazole hydrate (52mg, 0.38mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (74mg, 0.38mmol), N-isopropylmethylamine (28mg, 0.38mmol) and 4N NaOH (480. mu.L, 1.92mmol) were reacted to give 4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N-isopropyl-N-methyl-benzamide (18mg, 9%).

MS ESI：539.3[M+H]⁺

Example 50:

according to general procedure L, the starting material was purified by reaction of a mixture XIX (cf. scheme 6) containing 2- { [4- (2, 4-bis-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-benzoic acid and 2- { [4- (2-amino-4-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-benzoic acid (ratio 1: 2) (200mg, 0.32mmol), 1-hydroxybenzotriazole hydrate (52mg, 0.38mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (74mg, 0.38mmol), N-butylmethylamine (34mg, 0.38mmol) and 4N NaOH (480. mu.L, 1.92mmol) to give N-butyl-4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N-methyl-benzamide (16mg, 9%).

Example 51:

according to general procedure L, the starting material was purified by reaction of a mixture XIX (cf. scheme 6) containing 2- { [4- (2, 4-bis-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-benzoic acid and 2- { [4- (2-amino-4-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-benzoic acid (ratio 1: 2) (200mg, 0.32mmol), 1-hydroxybenzotriazole hydrate (52mg, 0.38mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (74mg, 0.38mmol), N-N-N' -trimethylenediamine (39mg, 0.38mmol) and 4N NaOH (480. mu.L, 1.92mmol) were reacted to give 4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N- (2-dimethylamino-ethyl) -N-methyl-benzamide (15mg, 8%).

MS ESI：568.3[M+H]⁺

Example 52:

according to general procedure L, the starting material was prepared by dissolving 2- { [4- (2, 4-bis-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-benzoic acid and 2- { [4- (2-amino-4-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-benzoic acid (ratio 1: 2) (200mg, 0.32mmol) in a mixture XIX (cf. scheme 6), 1-hydroxybenzotriazole hydrate (52mg, 0.38mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (74mg, 0.38mmol), dimethyl- (2-piperazin-1-yl-ethyl) -amine (60mg, 0.38mmol) and 4N NaOH (480 μ L, 1.92mmol) were reacted to give (4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -phenyl) - [4- (2-dimethylamino-ethyl) -piperazin-1-yl ] -methanone (10mg, 5%).

MS ESI：623.4[M+H]⁺

Example 53:

according to general procedure L, the starting material was purified by reaction of a mixture XIX (cf. scheme 6) containing 2- { [4- (2, 4-bis-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-benzoic acid and 2- { [4- (2-amino-4-isobutyrylamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-chloro-benzoic acid (ratio 1: 2) (200mg, 0.32mmol), 1-hydroxybenzotriazole hydrate (52mg, 0.38mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (74mg, 0.38mmol), 1- (2-methoxy-ethyl) -piperazine (55mg, 0.38mmol) and 4N NaOH (480. mu.L, 1.92mmol) were reacted to give 4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -phenyl) - [4- (2-methoxy-ethyl) -piperazin-1-yl ] -methanone (18mg, 9%).

MS ESI：610.6[M+H]⁺

Step M: reductive amination Using triethyl orthoformate

Triethyl orthoformate (2.8eq) and anthranilic acid derivative XI (1.2eq) were added to a solution of compound XVIII (1eq.) in isopropanol at room temperature under argon. The resulting mixture was stirred at 50 ℃ overnight. Sodium borohydride (4eq.) was then added at room temperature. The mixture was then stirred at 50 ℃ until the reaction was complete. The mixture was diluted with dichloromethane and saturated NaHCO₃The solution and brine washes. Over MgSO₄Dried above and the solvent evaporated under reduced pressure. The resulting compound (1eq.) was dissolved in methanol or isopropanol and an excess of 4N NaOH solution (6eq.) was added. The mixture was heated at 50 ℃ until after the reaction was complete. The reaction was quenched with water and extracted with dichloromethane. With saturated NaHCO₃The organic layer was washed with water, brine, MgSO₄Dried above and evaporated under reduced pressure. Purification by FC, CH₂Cl₂～CH₂Cl₂Gradient elution with/methanol (9/1) gave the compound.

Example 54:

according to the stepsStep M, by N- [5- (2-formyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -2-isobutyrylamino-pyrimidin-4-yl]-isobutyramide (200mg, 0.43mmol), 2-amino-N-carbamoylmethyl-4-chloro-N-methyl-benzamide (103mg, 0.43mmol), triethyl orthoformate (130. mu.L, 1.19mmol) and NaBH₄(64mg, 1.71mmol) to give N-carbamoylmethyl-4-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl]-amino } -N-methyl-benzamide (7mg, 3%).

MS ESI：554.1[M+H]⁺

General procedure N: coupling with anthranilic acid derivatives (scheme 7)

Compound XX (1eq.) and triethylamine (1.1eq.) are added stepwise to a solution of anthranilic acid derivative XI (1.1eq.) in acetonitrile at room temperature under argon. The resulting mixture was heated at 80 ℃ until the reaction was complete. To the mixture was added ethyl acetate and water, saturated NaHCO₃The organic layer was washed with the solution and brine. Over MgSO₄Dried above and the solvent evaporated under reduced pressure. Purification by FC, CH₂Cl₂～CH₂Cl₂Gradient elution with/methanol (93/7) afforded Compound I.

Example 55:

according to step N, by reacting 5- (2-chloromethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidine-2, 4-diamine hydrochloride (443mg, 1.15mmol), 2-amino-4-fluoro-N, N-dimethyl-benzamide (230mg, 1.26mmol), and triethylamine (175 μ L, 1.26mmol), 2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -4-fluoro-N, N-dimethyl-benzamide (20mg, 3.5%) was obtained.

MS ESI：495.0[M+H]⁺

Example 56:

by reacting 5- (2-chloromethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidine-2, 4-diamine hydrochloride (662mg, 1.71mmol), 2-amino-3-chloro-N, N-dimethyl-benzamide (375mg, 1.89mmol), and triethylamine (263. mu.L, 1.89mmol) according to step N, 3-chloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N, N-dimethyl-benzamide (20mg, 2.5%) was obtained.

MS ESI：511.2[M+H]⁺

Example 57:

by reacting 5- (2-chloromethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidine-2, 4-diamine hydrochloride (665mg, 1.72mmol), 2-amino-3, 5-dichloro-N, N-dimethyl-benzamide (440mg, 1.89mmol), and triethylamine (263. mu.L, 1.89mmol) according to step N, 3, 6-dichloro-2- { [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -N, N-dimethyl-benzamide (19.2mg, 2%) was obtained.

MS ESI：544.9[M+H]⁺

General procedure O: coupling with phenol (scheme 7)

To a solution of phenol XXI (1.5eq.) in DMF was added sodium hydride (60% in oil, 1.5eq.) at room temperature under argon. After stirring for 30 minutes, compound XX in DMF is added. The resulting mixture was stirred at room temperature until the reaction was complete. The excess reagent was evaporated under reduced pressure and the residue was dissolved in dichloromethane and saturated NaHCO₃The solution and brine washes. Over MgSO₄Dried above and the solvent evaporated under reduced pressure. Purification by FC, CH₂Cl₂～CH₂Cl₂Gradient elution with/methanol (9/1) afforded Compound I.

Example 58

Following general procedure O, 5- (2-chloromethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidine-2, 4-diamine hydrochloride (450mg, 1.16mmol), 3, 5-dichloro-2-hydroxy-N, N-dimethyl-benzamide (410mg, 1.75mmol), and sodium hydride (70mg, 1.75mmol) reacted to give 3, 5-dichloro-2- [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethoxy ] -N, N-dimethyl-benzamide (98mg, 15%).

MS ESI：547.2[M+H]⁺

Example 59:

following general procedure O, 4-chloro-2- [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethoxy ] -N-methyl-benzamide (36mg, 10%) was obtained by reacting 5- (2-chloromethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidine-2, 4-diamine hydrochloride (280mg, 0.72mmol), 4-chloro-2-hydroxy-N-methyl-benzamide (201mg, 1.09mmol) and sodium hydride (44mg, 1.09 mmol).

MS ESI：498.0[M+H]⁺

Example 60:

following general procedure O, by reacting 5- (2-chloromethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidine-2, 4-diamine hydrochloride (480mg, 1.24mmol), 5-fluoro-2-hydroxy-N, N-dimethyl-benzamide (342mg, 1.87mmol), and sodium hydride (75mg, 1.87mmol), 2- [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethoxy ] -5-fluoro-N, N-dimethyl-benzamide (44mg, 7%) was obtained.

MS ESI：496.2[M+H]⁺

Example 61:

following general procedure O, 4-chloro-2- [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethoxy ] -N, N-dimethyl-benzamide (1.3mg, 3.5%) was obtained by reacting 5- (2-chloromethyl-6, 7-dimethoxy-benzofuran-4-ylmethyl) -pyrimidine-2, 4-diamine hydrochloride (280mg, 0.72mmol), 4-chloro-2-hydroxy-N, N-dimethyl-benzamide (217mg, 1.09mmol) and sodium hydride (44mg, 1.09 mmol).

MS ESI：512.1[M+H]⁺

General procedure P: measurement of antibacterial Activity

The test for antibacterial susceptibility was carried out according to the procedure specified in National Committee for Clinical Laboratory Standards (NCCLS) [ M7-A5, 2001 ].

M7-A5 (2001): an antibacterial susceptibility dilution method against aerobically growing bacteria; approval Standard-fifth edition of national Standard.

General procedure Q: purified enzyme and assay of DHFR enzyme Activity

Baccarari & Joyner discloses that bacterial and human dihydrofolate reductase (dihydrofolate) results were purified and shown to function and were used in DHFR assays (Baccarari, D.P. & Joyner, S.S. 1981. dihydrofolate reductase and its effects on inhibitor binding enzymes. biochem.20, 1710-1716).

Claims

1. A compound of formula I

Formula I

Wherein

R¹To represent

Or

Wherein R is⁵Is cyano, carboxylic acid or

R¹⁰represents hydrogen or lower alkyl having 1 to 4 carbon atoms;

R⁹and R¹⁰Are linked through their nitrogen atoms to form a 3-, 4-, 5-or 6-membered heterocyclic ring, wherein the 5-or 6-membered ring optionally contains additional oxygen, nitrogen or sulfur heteroatoms which may be the same or different, wherein the nitrogen may be substituted by lower alkyl, mono-or dialkylaminoalkyl or alkoxyalkyl groups of 1 to 4 carbon atoms;

R⁷represents hydrogen or halogen;

R⁴represents hydrogen, lower alkyl having 1 to 4 carbon atoms;

and pharmaceutically acceptable salts thereof.

2. A compound of formula II

Formula II

Wherein

R²And R³Represents a methyl group;

R⁴represents hydrogen;

R⁵、R⁶、R⁷and R⁸As defined in formula I.

3. A compound of formula III

Formula III

Wherein

R²And R³Represents a methyl group;

R⁴represents hydrogen;

R⁵、R⁶、R⁷and R⁸As defined in formula I.

4. A compound of formula IV

Formula IV

Wherein

R²And R³Represents a methyl group;

R⁴represents hydrogen;

R⁵、R⁶、R⁷and R⁸As defined in formula I.

5. A compound of formula V

Formula V

Wherein

R²And R³Represents a methyl group;

R⁴represents hydrogen;

R⁵、R⁶and R⁷As defined in formula I.

6. A compound of formula VI

Formula VI

Wherein

R²And R³Represents a methyl group;

R⁴represents hydrogen;

R⁵、R⁶and R⁷As defined in formula I.

7. Compounds of formulae I, II, III, IV, V and VI wherein R⁵Are carboxylic acid dimethylamide, carboxylic acid carboxamide, carboxylic acid diethylamide, carboxylic acid methoxamide, pyrrol-1-yl-methanone, morpholin-4-yl-methanone, carboxylic acid carboxamide, piperidin-1-yl-methanone, carboxylic acid N- (1, 3, 5-trimethyl-1H-pyrazol-4-yl) -amide, carboxylic acid N-methyl-benzyl-amide, 4- (2-methoxy-ethyl) -piperazine 1-yl-methanone, 4- (2-dimethylamino-ethyl) -piperazine 1-yl-methanone, carboxylic acid N- (2-dimethylamino-ethyl) -N-methyl-amide, carboxylic acid N-butyl-methyl-amide, carboxylic acid N-butyl-methyl, Carboxylic acid N-isopropyl-N-methyl-amide, carboxylic acid N-carbamoylmethyl-N-methyl-amide, carboxylic acid or cyano;

R⁶represents hydrogen, fluorine, chlorine or methoxy;

R⁷represents hydrogen, fluorine or chlorine;

R⁸represents hydrogen or methyl.

8. A compound selected from the group consisting of:

4-chloro-2- [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -6, 7-dimethoxy-benzofuran-2-ylmethyl ] -amino } -benzonitrile

And pharmaceutically acceptable salts thereof.

9. Intermediates of the general formulae XI, XVII and XVIII

Wherein R is²、R³And R⁴The definition of formula I as defined in claim 1;

R¹¹represents a linear or branched lower alkyl group;

R¹²represents a lower alkyl group or an aryl group.

10. A pharmaceutical composition comprising one or more compounds as claimed in any one of claims 1 to 8 and customary inert carrier materials.

11. A pharmaceutical composition for the treatment of infections caused by gram-positive or gram-negative pathogens comprising one or more compounds according to any one of claims 1 to 8 and a usual inert carrier material.

12. Use of a compound according to any one of claims 1 to 8 as a medicament.

13. Use of a compound according to any one of claims 1 to 8 as a medicament for the treatment of infection.

14. Use of a compound according to any one of claims 1 to 8 as a medicament for the treatment of infections caused by gram-positive, gram-negative or mixed pathogens thereof.

15. Use of one or more compounds according to any one of claims 1 to 8 as active ingredients for the preparation of pharmaceutical compositions.

16. Use of one or more compounds according to any one of claims 1 to 8 as active ingredients for the preparation of pharmaceutical compositions for the treatment of infections.

17. Use of one or more compounds according to any one of claims 1 to 8 as active ingredients for the preparation of pharmaceutical compositions for the treatment of infections caused by gram-positive, gram-negative or mixed pathogens thereof.

18. A process for the preparation of a pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 8 as active ingredient, which comprises mixing the active ingredient or ingredients with pharmaceutically acceptable inert carrier materials and known auxiliaries.

19. A process for the preparation of a pharmaceutical composition for the treatment of infections caused by gram-positive, gram-negative or mixed pathogens thereof comprising one or more compounds according to any one of claims 1 to 8 as active ingredient, comprising mixing the active ingredient or ingredients with pharmaceutically acceptable inert carrier materials and known auxiliaries.