KR20120052095A - ??-phenyl-2-pyrimidine isothiocyanate derivatives and preparation process thereof - Google Patents

Abstract

PURPOSE: An N-phenyl-2-pyrimidine isothiocyanate derivative compound is provided to suppress influenza virus and to prevent and treat viral infection. CONSTITUTION: An N-phenyl-2-pyrimidine isothiocyanate derivative compound is denoted by chemical formula 1. A method for preparing the compound of chemical formula 1 comprises: a step of reacting a compound of chemical formula 4a or 4b with a compound of chemical formula 5 to prepare a compound of chemical formula 6a or 6b; and a step of removing PG.

Description

Ν-phenyl-2-pyrimidine isothiocyanate derivative and its manufacturing method {Ν-phenyl-2-pyrimidine isothiocyanate derivatives and preparation process

The present invention provides a novel N-phenyl-2-pyrimidine iso useful for the treatment and prevention of infections of influenza and similar viruses susceptible to inhibitory activity against strains of influenza virus and replication inhibitors of viruses that block replication of the virus. It relates to a thiocyanate derivative. The present invention also relates to methods of using these compounds for the treatment or prevention of influenza and similar viral infections, compositions comprising these compounds and methods of preparing these compounds.

Bird flu is spreading worldwide, but the only weapons against it are M2 ion channel blockers and neuraminidase inhibitors. In recent years, the problem of resistance to these drugs is intensifying, and new drug development is more urgent than ever. There are only a few currently approved pharmaceutical products for treating influenza. The first class of drugs include M2 ion channel blockers, such as amantadine or rimantadine, which are only active against the influenza virus Hemagglutinin virus strain. Interfere with the cloning process. The second class of drugs are oseltamivir (oseltamivir, Korean Patent Publication No. 10-1998-0703600) or zanamivir (zanamivir, which are registered only for the influenza virus Neuraminidase virus strain). 0169496) The same neuraminidase inhibitor acts to prevent the virus from replicating the host cell. The two classes of therapies intervene in one part of the influenza virus infection process and act to disrupt the process to inhibit the growth of the virus.

In addition to the neuraminidase inhibitors mentioned above, inhibitors are also disclosed, in particular based on 5- and 6-membered carbocyclic ring systems. Examples include Laninamivir (Laninamivir, Korean Patent No. 10-0506578), Feramivir (US Patent 6562861). Recently, however, mutant viruses resistant to these drugs, which are being used as antiviral drugs, are rapidly emerging, and zanamivir can be administered only by inhalation. Therefore, there is a great need for improved drugs for the treatment and prevention of influenza infections.

The inventors have continued their research to provide novel N- with superior influenza virus inhibitory activity that can treat or prevent diseases caused by influenza virus as an antiviral agent that is superior to the prior art and has the effect of preventing the replication of the virus. The phenyl-2-pyrimidine isothiocyanate compounds were surprisingly invented.

The present invention provides a novel N-phenyl-2-pyrimidine isothiocyanate derivative of Formula 1, or a hydrate, solvate, pharmaceutically acceptable salt, prodrug, complex, diastereomer or enantiomer thereof It is.

Formula 1

In the above formula

R1 represents thiazole, aminothiazole, imidazole, 2-methylimidazole, 4-methylimidazole, pyrazine, 2-methylpyrazine, or pyridine, R2 represents H, lower alkyl or lower alkoxy, R 3 or R 4 may be each independently substituted with a radical of Formula 2 or Formula 3,

Formula 2

Formula 3

Wherein R 5 represents a saturated or unsaturated monocyclic radical which optionally represents an aliphatic having 2 to 10 carbon atoms or contains 1 to 5 heteroatoms selected from nitrogen, oxygen, sulfur or halogen and contains 5 to 7 ring members or optionally A group in which the benzene ring represents a non- or tri-cyclic radical fused, or a ring member containing 3 to 10 carbon atoms and selected as lower alkyl, lower carbonyl, lower halo alkyl, independent halogen, or lower alkoxy as substituents; It represents a saturated or unsaturated ring radical containing, piperidinyl or piperazinyl, which may be substituted by lower alkyl, or phenyl radicals, which may be substituted by lower alkyl.

The invention also relates to a composition comprising one or more compounds of the invention and a pharmaceutically acceptable carrier or excipient.

The invention also relates to pharmaceutical compositions for the treatment or prophylaxis of viral infections, comprising one or more compounds of the invention and a pharmaceutically acceptable carrier or excipient.

The invention also relates to the use of a compound of the invention, or a hydrate, solvate, pharmaceutically acceptable salt, prodrug, complex, diastereomer or enantiomer thereof, for the preparation of a pharmaceutical composition for the treatment or prevention of a viral infection. It is about.

The invention also provides a therapeutically effective amount of a compound of the invention, or a hydrate, solvate, pharmaceutically acceptable salt, prodrug, complex, diastereomer or enantiomer thereof, for a person in need of treatment or prevention of a viral infection. It relates to a method for preventing or treating a viral infection comprising administering to a mammal, including.

Hereinafter, the present invention will be described in more detail.

Many of the neuraminidase-bearing organisms are the major pathogens of humans and animals and cause serious diseases such as influenza virus, New Cow's disease virus, and poultry fest virus.

In general, many predicted that neuraminidase activity inhibitors could prevent infection by neuraminidase bearing viruses. For example, representative therapeutic agents used until recently as neuraminidase inhibitors include oseltamivir (Korean Patent Publication No. 10-1998-0703600) and zanamivir (zanamivir, Korean Patent Publication No. 0169496). These agents act to inhibit cycle replication of influenza viruses.

The inventors have discovered N-phenyl-2-pyrimidine isothiocyanenit derivatives, which are compounds of formula (I), having higher activity than the corresponding oseltamivir phosphate.

Thus, as a particularly preferred aspect, the present invention provides a compound of formula 1 and pharmaceutically acceptable derivatives thereof.

Formula 1

Wherein R 1, R 2, R 3 and R 4 are as defined above.

In the present invention, reference to "compounds of Formula I" (or "compounds of the present invention", etc.), unless otherwise specified, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, complexes, moieties thereof It is understood to include pharmaceutically acceptable derivatives of the compound of formula 1, including stereoisomers or enantiomers.

In the present invention, the term "lower alkyl" preferably refers to a straight or branched chain saturated aliphatic hydrocarbon radical comprising 1 to 12, alternatively 1 to 8 carbon atoms, alternatively 1 to 6 carbon atoms. Examples of the alkyl radical include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tert-butyl, pentyl, isoamyl, n-hexyl, and the like. It is not limited to this. The alkyl group of the present invention may be optionally substituted.

The term "alkoxy" also means an oxygen moiety that additionally has an alkyl substituent. The alkoxy group of the present invention may be optionally substituted.

The term "aliphatic" radical also means alkenyl, alkynyl, or alkyl. Here, the term "alkenyl" refers to an unsaturated straight or branched chain aliphatic group of one or more carbon-carbon double bonds having 2 to 12 carbon atoms, alternatively 2 to 8 carbon atoms, alternatively 2 to 6 carbon atoms. It is intended to mean. Non-limiting examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, and hexenyl. The term "alkynyl" refers to an unsaturated straight or branched chain aliphatic group of one or more carbon-carbon triple bonds having 2 to 12 carbon atoms, alternatively 2 to 8 carbon atoms, alternatively 2 to 6 carbon atoms It is intended to be. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

In addition, the term "halogen" denotes a fluoro, chlorine, bromine or iodine atom, preferably fluoro, chlorine.

The compounds of the present invention also include salts within the scope of the present invention. Compounds of the invention, for example compounds of formula 1, are understood to mean salts thereof unless otherwise indicated.

As used herein, the term "salt" refers to an acidic and / or basic salt form formed of organic and / or organic acids and bases. Salts of the compounds of the invention can be formed, for example, by reacting the compounds of the invention with an amount of acid or base, such as an equivalent amount, in an aqueous medium in which the salt precipitates, and then lyophilizing.

Examples of such salts include, but are not limited to: salts formed with inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid Salts formed with ascorbic acid, benzoic acid, tannic acid, palmoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and polygalacturonic acid.

As used herein, the term "pharmaceutically acceptable derivative" refers to hydrates, solvates, pharmaceuticals of the compounds of the present invention that retain the desired biological activity of the compound and exhibit minimal or no undesirable toxicological effects. Are intended to mean acceptable salts, prodrugs, complexes, diastereomers or enantiomers.

Some compounds of the present invention may have chiral centers and / or geometric isomeric centers (E- and Z-isomers), and the present invention includes all such optical isomers, enantiomers, diastereomers, and geometric isomers. It is understood that. When the compounds of the present invention comprise chiral centers, the present invention relates to enantiomeric and / or diastereomericly pure isomers of such compounds, enantiomeric and / or diastereomericly rich mixtures of such compounds. , And racemic and scalem mixtures of such compounds.

The chiral centers of the invention may have an S or R configuration. Racemic forms can be separated by physical methods such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. Individual optical isomers can be obtained starting from chiral precursors / intermediates or racemates by any suitable method including, but not limited to, conventional methods such as salt formation with optically active acids, and then crystallization.

The invention also includes prodrugs of the compounds of the invention. The term “prodrug” is intended to denote a compound covalently bound to a carrier, which prodrug may release the active ingredient when administered to a mammalian subject. Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to those skilled in the art. These techniques modify appropriate functional groups in certain compounds. However, these modified functional groups regenerate the original functional groups in routine manipulation or in vivo. Examples of prodrugs include, but are not limited to, esters (eg, acetate, formate, and benzoate derivatives) and the like.

The compounds of the present invention have an inhibitory activity against strains of influenza virus and exhibit excellent effects in the treatment and prevention of infections of influenza and similar viruses thereof, which are susceptible to virus replication inhibitors that block the replication of viruses.

In one embodiment of the present invention, preferred compounds of formula (1) of the present invention, when the radicals of formula (2) or (3) are each substituted with R3, R2 and R4 each represent hydrogen, and the radicals of formula (2) or (3) When R 4 is each substituted, R 2 represents methyl and R 3 represents hydrogen.

In one embodiment of the present invention, among the compounds of Formula 1, a preferred compound, R 1 represents pyrazine, pyridine, or thiazole, and R 3 or R 4 may be substituted with a radical of Formula 2 or Formula 3, respectively. Here, when the radicals of formula (2) or (3) are each substituted with R3, R2 represents hydrogen or methyl, R4 represents hydrogen, and when the radicals of formula (2) or formula (3) are each substituted with R4, R2 is Hydrogen or methyl, and R3 is hydrogen.

Formula 2

Formula 3

Wherein R 5 is as defined above.

In one embodiment of the invention, more preferred compounds are those wherein R 2 represents hydrogen or methyl, R 4 represents hydrogen, and R 5 represents methylpiperidine, phenyl when the radicals of formula 2 or 3 are each substituted with R 3. , A phenyl, 1-benzylpiperidine, or 1-benzyl-4-ethylpiperazin group substituted with alkyl. In view of virus inhibition of influenza, in particular, a structure in which R1 is pyridine or pyrazine, R2 and R4 are hydrogen, and R5 has methylpiperidine is preferred.

In one embodiment of the invention, more preferred compounds are those wherein R 2 represents hydrogen or methyl, R 3 represents hydrogen and R 5 represents methylpiperidine, phenyl when the radical of formula 2 or , A phenyl, 1-benzylpiperidine, or 1-benzyl-4-ethylpiperazin group substituted with alkyl. In view of virus inhibition of influenza, in particular, compounds of formula (1) in which R 1 is thiazole, pyridine, pyrazine, R 3 is hydrogen and R 5 is methylpiperidine, benzyl, 1-benzylpiperidine are preferred. .

The method for preparing the compound of Formula 1 according to the present invention may be prepared through three synthetic processes. Isomers and solvates (eg hydrates) of the compounds of formula 1 are also within the scope of the present invention. Methods of solvation are commonly known in the art. Thus, the compounds of the present invention may be in free hydrate or salt form and can be obtained by the method illustrated by the following scheme.

In the first preparation method, a compound of Formula 4a or 4b is reacted with a compound of Formula 5 to produce a compound of Formula 6a or 6b, and PG, which is a protecting group, is released to generate a compound of Formula 7a or 7b. Compounds of the invention can be prepared:

4a

4b

Formula 5

Formula 6a

Formula 6b

Formula 7a

Formula 7b

In the above formula

R1 to R5 are as defined above,

PG represents an amine protecting group, preferably thibutyldicarbonate, benzyloxycarbonyl or toluenesulfonyl group.

In a second manufacturing method according to the present invention, the compound of Chemical Formula 1 is reacted with the compound of Chemical Formula 4a or Chemical Formula 4b to produce a compound of Chemical Formula 9a or Chemical Formula 9b, Compounds of the present invention may be prepared by reacting with a compound to generate Formula 11a or Formula 11b:

Formula 8

Formula 9a

Formula 9b

Formula 10

Formula 11a

Formula 11b

In the above formula

R1 to R5 and Y are as defined above, X represents halogen, preferably fluoro, or chlorine,

R6 represents phenyl substituted with lower alkyl or lower alkyl

Y represents piperazine substituted with piperidine, piperazine, or lower alkyl.

In a third method according to the present invention, the compound of Formula 1 is reacted with a compound of Formula 12a or 12b to a compound of Formula 13 to generate a compound of Formula 14a or 14b, and leaves PG as a protecting group. Compounds of the present invention may be prepared by producing compounds 15a or 15b.

Formula 12a

Formula 12b

Formula 13

Formula 14a

Formula 14b

Formula 15a

Formula 15b

In the above formula

R1 to R5 are as defined above and PG represents an amine protecting group, preferably thibutyldicarbonate, benzyloxycarbonyl or toluenesulfonyl group.

Therefore, it is another object of the present invention to provide such a manufacturing method.

N-phenyl-2-pyrimidine isothiocyanate derivative of the general formula (1) of the present invention can be prepared as shown by the following three equations.

Equation 1

In the scheme 1, R1 to R5 and PG are as defined above.

Aniline compounds (Ia, Ib) substituted with N-phenyl-2-pyrimidine are disclosed in Korean Patent No. 10-0565002 and US Patent (US 7595323). Compound (II) comprising aniline compounds (Ia, Ib) and organic acid groups and protected with the other amine is prepared, and then diethylcyanophosphonate (DECP) or 1-ethyl-3- (3) in the presence of a base. Amide compounds (IIIa, IIIb) can be prepared using '-dimethylaminopropyl) carbodiimide hydrochloride (EDCl). Compound (IIIa, IIIb) was deprotected with protecting group (PG) using an acid to synthesize amine compounds (IVa, IVb), where N-phenyl-2-pyrimidine was substituted using a base and carbon disulfide. It is possible to prepare a compound of formula (I) which is an isothiocyanate derivative.

Equation 2

In the scheme 2, R1 to R4, R6 and X are as defined above.

Compound (V) in which aniline compound (Ia, Ib) substituted with N-phenyl-2-pyrimidine and phenyl in which R6 is substituted with lower alkyl or lower alkyl, containing organic acid groups and the other substituted with halogen (V) Is reacted with 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCl) in the presence of a base to give the amide compounds (VIa, VIb). An amine compound (VIIa, VIIb) is produced by reacting a compound (VII) where Y represents piperidine, piperazine, or piperazine substituted with alkyl under a base. An amine compound (VIIa, VIIb) can be prepared using a carbon disulfide under a base, wherein the compound of formula (I) is an isothiocyanate derivative substituted with N-phenyl-2-pyrimidine.

Equation 3

In the scheme 3, R1 to R5 and PG are as defined above.

N-phenyl-2-pyrimidine-substituted benzoic acid compounds (Xa, Xb) are disclosed in Korean Patent No. 10-0674813 and US Patent (US 7501424). Synthesis method similar to that of the formula 1 was obtained by diethylcyanophosphonate (DECP) or 1-ethyl- containing a compound (VIIa, Xb) and an amine group and the other protected amine compound (VII) in the presence of a base. Compounds (a, b) were prepared using 3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCl), and then deprotected the protecting group (PG) with an acid using an acid, similar to the formula (1). Compounds (a) and (b) may be synthesized, and a compound of Formula 1 may be prepared, which is an isothiocyanate derivative in which N-phenyl-2-pyrimidine is substituted using carbon disulfide under a base.

The preparation method according to the invention may preferably be carried out in the presence of a base or an acid in a solvent. At this time, the solvent, acid, and base may use any conventional solvent, base or acid catalyst which does not adversely affect the reaction, but for example, as a solvent, tetrahydrofuran, methylene chloride and ethanol, N, N-dimethylformamide At least one selected from N, N-dimethylacetamide, ethyl acetate, tert-butanol, toluene, dioxane, and pyridine and triethylamine, diethylamine, sodium carbonate, potassium carbonate and sodium hydroxide as bases. 1 selected from potassium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium aluminum hydride, lithium borohydride, sodium nitrate cesium carbonate At least one species selected from trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid, bromic acid, acetic acid, etc. Mention may be made of the organization.

Starting materials used in the preparation of the compounds according to the present invention according to the method are all commercially available, or the Republic of Korea Patent No. 10-0565002, Republic of Korea Patent No. 10-0674813, US Patent (US 7595323) and US Patent (US) 7501424) and the like, which can be easily manufactured and can be easily used for purchase. The reaction can usually be carried out under cooling or warming, and after completion of the reaction, the final compound can be purified through conventional post-treatment processes such as column chromatography, recrystallization, and the like.

On the other hand, the present invention relates to a pharmaceutical composition for the treatment or prevention of viral infections, comprising administering an effective amount of a compound of formula (1) or a pharmaceutically acceptable derivative thereof to a mammal, including humans, and particularly has an effect on influenza infection It can be effectively used for the treatment of such diseases.

Typical suitable dosages in single or separate doses required for the treatment of the compounds of the present invention as such have been shown to be effective range from about 0.01 to 750 mg / kg body weight per day, preferably 0.1 to 100 mg, most preferred Preferably, the dosage ranges from 0.5 to 25 mg, but specific dosage levels for individual patients vary depending on the specific compound to be used, the weight of the patient, sex, diet, time of administration of the drug, method of administration, excretion rate, drug mixture, and the condition and age of the patient. Can be.

The compound of the present invention may be administered as it is during processing, but is preferably provided as a pharmaceutical formulation.

Accordingly, the present invention provides a pharmaceutical formulation comprising admixing a compound of formula 1 or a pharmaceutically acceptable derivative thereof with a pharmaceutically acceptable carrier and / or excipient.

In addition, the compounds of the present invention may be administered by any route as desired, but injection and oral administration are preferred.

Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, can be prepared using suitable dispersing agents, wetting agents or suspending agents according to known techniques. Solvents that can be used for this are water, Ringer's solution and isotonic NaCl solution, and sterile fixed oils are also commonly used as solvents or suspending media. Any non-irritating fixed oil may be used for this purpose, including mono- and diglycerides, and fatty acids such as oleic acid may also be used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Particularly, capsules and tablets are useful. Tablets and pills are preferably prepared with enteric agents. Solid dosage forms can be prepared by mixing the active compound of formula 1 according to the present invention with a carrier such as one or more inert diluents such as sucrose, lactose, starch and the like, lubricants such as magnesium stearate, disintegrants, binders and the like. .

Compounds of the present invention have inhibitory activity against strains of influenza virus and have activity against the same virus in the purpose of treating and preventing infections of influenza and similar viruses susceptible to neuraminidase inhibitors. May be used in conjunction with a second therapeutic agent. The compound may be used as a combination, for example, zanamivir, amantadine, rimantadine, and the like, and the dosage of each compound may be the same as or different from the dosage used when each compound is used alone.

Hereinafter, the present invention will be described in more detail based on the following Preparation Examples and Examples. However, these preparation examples and examples are only intended to help the understanding of the present invention, it is not intended that the scope of the present invention is limited to these in any sense.

Preparation Example 1

Synthesis of thi-butyl 4- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenylamino) -4-oxobutylcarbamate

6-methyl-N1- (4- (pyridin-3-yl) pyrimidin-2-yl) benzene-1,3-diamine (0.90 g, 2.00 mmol) and 4- (thi-butoxycarbonylamino) buta Noric acid (0.41 g, 2.00 mmol) was dissolved in dimethylformimide (10 mL), cooled to 0-5 ^o C, diethylcyanophosphonate (0.40 g, 2.40 mmol), triethylamine (0.65 g, 6.00 mmol) was added and stirred at 90˜100 ^° C. for 6 hours. After the reaction was completed, ethyl acetate (30 mL) was added and washed with 1N sodium hydroxide (30 mL), purified water (30 mL) and saturated aqueous sodium chloride solution (30 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Ethyl acetate (10 mL) was added thereto, stirred for 1 hour, and filtered to obtain the target compound (0.68 g, 1.48 mmol, 74%) as a brown solid.

¹ H-NMR (400 MHz, DMSO _, δ) = 1.37 (s, 9H), 1.70 (m, 2H), 2.17 (s, 3H), 2.29 (t, 3H), 2.97 (q, 2H), 6.86 ( t, 3H), 7.14 (d, 1H), 7.29 (dd, 1H), 7.42 (d, 1H), 7.53 (q, 1H), 7.92 (d, 1H), 8.47 (m, 1H), 8.51 (d , 1H), 8.92 (s, 1H), 9.26 (m, 1H), 9.83 (s, 1H)

Production Example 2

Synthesis of 4-amino-N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) butanamide

Thi-butyl 4- (4-methyl-3- (4- (pyridin-3-yl) pyrimidine-2-ylamino) phenylamino) -4-oxobutylcarbamate (0.60 g, 1.43 mmol) in triples After dissolving in roacetic acid (10 mL) and stirred at room temperature for 2 hours. When the reaction was completed, the reaction was concentrated under reduced pressure. Dichloromethane (5mL) was added thereto, the solid was dissolved, washed with saturated sodium bicarbonate (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography to give a pale yellow solid target compound (0.42g, 1.16mmol, 81%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.66 (q, 2H), 2.20 (s, 3H), 2.34 (t, 3H), 2.59 (t, 3H), 7.14 (d, 1H), 7.30 ( dd, 1H), 7.41 (d, 1H), 7.24 (dd, 1H), 7.95 (d, 1H), 8.46 (tt, 1H), 8.50 (d, 1H), 8.69 (dd, 1H), 8.96 (s , 1H), 9.27 (d, 1H), 9.90 (s, 1H)

Production Example 3

Synthesis of thi-butyl 4- (4-methyll-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenylamino) -4-oxobutylcarbamate

Similar to Preparation Example 6, 6-methyl-N1- (4- (thiazol-2-yl) pyrimidin-2-yl) benzene-1,3-diamine (0.71 g, 2.50 mmol) and 4- (ti- Butoxycarbonylamino) butanoic acid (0.51 g, 2.50 mmol) was dissolved in dimethylformimide (10 mL), diethylcyanophosphonate (0.50 g, 3.00 mmol) and triethylamine (0.76 g, 7.5 mmol). ) To give a pale yellow solid target compound (0.84g, 1.79mmol, 72%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.37 (s, 9H), 1.70 (m, 2H), 2.17 (s, 3H) 2.29 (t, 3H), 2.97 (q, 2H), 7.13 (d , 1H), 7.34 (dd, 1H), 7.40 (d, 1H), 7.72 (d, 1H), 7.96 (d, 1H), 8.04 (d, 1H), 8.52 (d, 1H), 9.12 (s, 1H), 9.94 (s, 1H)

Manufacturing example  4

Synthesis of 4-amino-N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) butanamide

Similar to Preparation 2, thi-butyl 4- (4-methyll-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenylamino) -4-oxobutylcarbamate (0.80 g, 1.71 mmol) and trifluoroacetic acid (8 mL) were used to obtain the title compound (0.56 g, 1.52 mmol, 89%) as a pale yellow solid.

¹ H-NMR (400 MHz, DMSO _, δ) = 1.77 (m, 2H), 2.17 (s, 3H), 2.37 (t, 2H), 2.73 (t, 2H), 7.15 (d, 1H), 7.35 ( dd, 1H), 7.38 (d, 1H), 7.73 (d, 1H), 7.96 (d, 1H), 8.06 (d, 1H), 8.52 (d, 1H), 9.12 (s, 1H), 9.93 (s , 1H)

Manufacturing example  5

Synthesis of thi-butyl 4- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) benzamido) benzylcarbamate

Similar to Preparation 1, 4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) benzoic acid (1.00 g, 3.42 mmol) and thi-butyl 4-aminobenzylcarbamate (0.70 g, 3.42 mmol) ) Was dissolved in dimethylformimide (10 mL), and then pale yellow target compound (1.34 g, 2.70) was obtained using diethylcyanophosphonate (0.68 g, 4.10 mmol) and triethylamine (1.38 g, 10.26 mmol). mmol, 79%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.39 (s, 9H), 4.09 (d, 2H), 7.20 (d, 2H), 7.35 (t, 1H), 7.58 (m, 2H), 7.71 ( d, 2H), 7.98 (s, 4H), 8.52 (tt, 1H), 8.66 (d, 1H), 8.74 (dd, 1H), 9.37 (d, 1H), 10.06 (s, 1H), 10.13 (s , 1H)

Manufacturing example  6

Synthesis of N- (4- (aminomethyl) phenyl) -4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) benzamide

Similar to Preparation Example 2, thi-butyl 4- (4- (4- (pyridin-3-yl) pyrimidine-2-ylamino) benzamido) benzylcarbamate (1.0 g, 2.0 mmol) and trifluoro Acetic acid (10 mL) was used to obtain a pale yellow solid target compound (0.73 g, 1.85 mmol, 92%).

¹ H-NMR (400 MHz, DMSO _, δ) = 3.72 (d, 2H), 7.35 (m, 2H), 7.57 (m, 2H), 7.70 (t, 2H), 7.98 (s, 4H), 8.50 ( tt, 1H), 8.64 (t, 1H), 8.73 (dd, 1H), 9.35 (d, 1H), 10.11 (s, 1H), 10.20 (s, 1H)

Manufacturing example  7

Synthesis of thi-butyl 4- (4-methyl-3- (4- (pyridine-3-) pyrimidin-2-ylamino) benzamido) benzylcarbamate

Similar to Preparation 1, 4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) benzoic acid (1.00 g, 3.27 mmol) and thi-butyl 4-aminobenzylcarbamate (0.73 g, 3.27 mmol) was dissolved in dimethylformimide (10 mL), followed by diethylcyanophosphonate (0.65 g, 3.92 mmol) and triethylamine (0.99 g, 9.87 mmol) to give a pale yellow solid. (1.15 g, 2.26 mmol, 69%) was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 1.39 (s, 9H), 2.38 (s, 3H), 4.09 (d, 2H), 7.38 (d, 1H), 7.40 (d, 1H), 7.47 ( d, 1H), 7.59 (m, 2H), 7.72 (s, 1H), 7.83 (d, 2H), 8.24 (s, 1H), 8.46 (d, 1H), 8.59 (d, 1H), 8.74 (dd , 1H), 9.15 (s, 1H), 9.29 (d, 1H), 10.49 (s, 1H)

Manufacturing example  8

Synthesis of N- (4- (aminomethyl) phenyl) -4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) benzamide

Similar to Preparation 2, thi-butyl 4- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) benzamido) benzylcarbamate (1.0 g, 1.96 mmol) To give a pale brown solid target compound (0.68g, 1.65mmol, 84%) using acrylonitrile (10mL).

¹ H-NMR (400 MHz, DMSO _, δ) = 2.35 (s, 3H), 3.74 (s, 2H), 7.29 (d, 1H), 7.41 (d, 1H), 7.42 (d, 1H), 7.54 ( q, 1H), 7.72 (s, 1H), 7.83 (d, 2H), 8.24 (s, 1H), 8.46 (d, 1H), 8.51 (d, 1H), 8.82 (dd, 1H), 9.10 (s , 1H), 9.29 (d, 1H), 10.36 (s, 1H)

Manufacturing example  9

(S) -Ty-butyl 1- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenylamino) -1-oxo-3-phenylpropan-2-yl Synthesis of Carbamate

Similar to Preparation Example 1 6-methyl-N1- (4- (pyridin-3-yl) pyrimidin-2-yl) benzene-1,3-diamine (1.0 g, 3.6 mmol) and (R) -2- (T-butoxycarbonylamino) -3-phenylpropanoic acid (0.96 g, 3.6 mmol) was dissolved in dimethylformimide (10 mL), followed by diethylcyanophosphonate (0.72 g, 4.32 mmol) and tri Ethylamine (1.09 g, 10.8 mmol) was used to obtain a pale yellow solid target compound (1.23 g, 2.34 mmol, 65%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.35 (s, 9H), 2.19 (s, 3H), 2.84 (m, 1H), 3.01 (m, 1H), 4.33 (m, 1H), 7.26 ( m, 2H), 7.37 (m, 5H), 7.40 (d, 1H), 7.73 (s, 1H), 7.94 (d, 1H), 8.07 (d, 1H), 8.54 (d, 1H), 9.14 (s , 1H), 9.98 (s, 1H)

Manufacturing example  10

Synthesis of (S) -2-amino-N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) -3-phenylpropanamide

Similarly to Preparation Example 2, (S) -Ty-Butyl 1- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenylamino) -1-oxo-3- Phenylpropane-2-ylcarbamate (1.00 g, 1.91 mmol) and trifluoroacetic acid (10 mL) were used to obtain a pale brown solid target compound (0.74 g, 1.73 mmol, 91%).

¹ H-NMR (400 MHz, DMSO _, δ) = 2.18 (s, 3H), 2.70 (q, 1H), 3.02 (q, 1H), 3.56 (q, 1H), 7.26 (m, 2H), 7.29 ( m, 4H), 7.39 (m, 2H), 7.74 (d, 1H), 7.97 (d, 1H), 8.07 (d, 1H), 8.55 (d, 1H), 9.17 (s, 1H), 9.80 (s , 1H)

Preparation Example 11

Synthesis of thi-butyl 4- (4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) benzamido) phenylcarbamate

Similar to Preparation 1, 4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) benzoic acid (0.6 g, 1.95 mmol) and thi-butyl 4-aminophenylcarbamate (0.41 g, 1.95 mmol) was dissolved in dimethylformimide (10 mL), and then pale yellow target compound (0.39 g, 2.34 mmol) and triethylamine (0.59 g, 5.85 mmol) were used. 0.52 g, 1.21 mmol, 62%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.35 (s, 9H), 2.36 (s, 3H), 7.44 (d, 1H), 7.64 (d, 1H), 7.76 (dd, 1H), 8.06 ( dd, 2H), 8.32 (d, 1H), 8.63 (d, 1H), 8.77 (t, 2H), 9.26 (s, 1H), 9.04 (s, 1H), 10.74 (s, 1H)

Production Example 12

Synthesis of N- (4-aminophenyl) -4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) benzamide

4-Methyl-N- (4-nitrophenyl) -3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) benzamide (0.50 g, 1.17 mmol) and trifluoroacetic acid (10 mL) To obtain a pale yellow solid target compound (0.38g, 0.95mmol, 81%).

¹ H-NMR (400 MHz, DMSO _, δ) = 2.32 (s, 3H), 4.92 (S, 2H), 6.53 (d, 2H), 7.37 (m, 3H), 7.61 (d, 1H), 7.71 ( d, 1H), 8.24 (s, 1H), 8.61 (d, 1H), 8.76 (s, 2H), 9.22 (s, 1H), 9.40 (s, 1H), 9.84 (s, 1H)

Production Example 13

Synthesis of thi-butyl 4- (4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) benzamido) benzylcarbamate

Similar to Preparation 1, 4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) benzoic acid (1.0 g, 3.25 mmol) and thi-butyl 4-aminobenzylcarbamate (0.73 g, 3.25 mmol) was dissolved in dimethylformimide (10 mL), and then pale brown target compound (1.26) was obtained using diethylcyanophosphonate (0.65 g, 3.90 mmol) and triethylamine (0.99 g, 9.75 mmol). g, 2.47 mmol, 76%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.38 (s, 9H), 2.34 (s, 3H), 4.08 (d, 2H), 7.20 (d, 2H), 7.34 (t, 1H), 7.41 ( d, 1H), 7.36 (d, 1H), 7.71 (d, 2H), 7.74 (dd, 1H), 8.27 (d, 1H), 8.62 (d, 1H), 8.78 (d, 2H), 9.24 (s , 1H), 9.40 (s, 1H), 10.15 (s, 1H)

Preparation Example 14

Synthesis of N- (4- (aminomethyl) phenyl) -4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) benzamide

Similar to Preparation 2, thi-butyl 4- (4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) benzamido) benzylcarbamate (1.00 g, 1.96 mmol) And trifluoroacetic acid (10 mL) were used to obtain a pale yellow solid target compound (0.68 g, 1.64 mmol, 84%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.65 (s, 2H), 2.33 (s, 3H), 3.66 (d, 2H), 7.25 (d, 2H), 7.39 (d, 1H), 7.59 ( d, 1H), 7.70 (d, 2H), 7.75 (dd, 1H), 8.28 (s, 1H), 8.60 (d, 1H), 8.76 (s, 2H), 9.40 (s, 1H)

Preparation Example 15

Synthesis of thi-butyl 4- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) benzamido) benzylcarbamate

Similar to Preparation Example 1, 4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) benzoic acid (0.74 g, 2.37 mmol) and thi-butyl 4-aminobenzylcarbamate ( 0.53 g, 2.37 mmol) was dissolved in dimethylformimide (10 mL), and then pale brown target compound was obtained using diethylcyanophosphonate (0.47 g, 2.84 mmol) and triethylamine (0.72 g, 7.11 mmol). (1.03 g, 1.99 mmol, 84%) was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 1.39 (s, 9H), 2.33 (s, 3H), 4.09 (d, 2H), 7.20 (d, 2H), 7.35 (t, 1H), 7.40 ( d, 1H), 7.43 (d, 1H), 7.70 (d, 2H), 7.74 (dd, 1H), 7.92 (d, 1H), 8.05 (d, 1H), 8.19 (d, 1H), 8.56 (d , 1H), 9.27 (s, 1H), 10.14 (s, 1H)

Production Example 16

Synthesis of N- (4- (aminomethyl) phenyl) -4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) benzamide

Similar to Preparation 2, thi-butyl 4- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) benzamido) benzylcarbamate (0.90 g, 1.74 mmol ) And trifluoroacetic acid (10 mL) were used to obtain a pale yellow solid target compound (0.64 g, 1.53 mmol, 88%).

¹ H-NMR (400 MHz, DMSO _, δ) = 2.32 (s, 3H), 3.67 (s, 2H), 7.26 (d, 2H), 7.40 (m, 2H), 7.43 (d, 1H), 7.70 ( m, 3H), 7.93 (d, 1H), 8.05 (d, 1H), 8.16 (s, 1H), 8.56 (d, 1H), 9.27 (s, 1H), 10.11 (s, 1H)

Manufacturing example  17

(S) -Ty-butyl 1- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenylamino) -1-oxo-3-phenylpropane-2- Synthesis of Nylcarbamate

Similar to Preparation Example 1 6-methyl-N1- (4- (thiazol-2-yl) pyrimidin-2-yl) benzene-1,3-diamine (0.74 g, 2.60 mmol) and (R) -2 -(Ti-butoxycarbonylamino) -3-phenylpropanoic acid (0.69 g, 2.60 mmol) was dissolved in dimethylformimide (10 mL), followed by diethylcyanophosphonate (0.52 g, 3.12 mmol). Light brown target compound (1.10 g, 2.08 mmol, 80%) was obtained using triethylamine (0.79 g, 7.80 mmol).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.35 (s, 9H), 2.19 (s, 3H), 2.84 (m, 1H), 3.01 (m, 1H), 4.33 (m, 1H), 6.19 ( t, 1H), 6.22 (t, 1H), 7.06 (d, 1H), 7.16 (t, 2H), 7.27 (t, 2H), 7.37 (m, 4H), 7.75 (s, 1H), 7.94 (d , 1H), 8.08 (d, 1H), 8.54 (d, 1H), 9.15 (s, 1H), 10.12 (s, 1H)

Manufacturing example  18

Synthesis of (S) -2-amino-N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) -3-phenylpropanamide

Similar to Preparation 2, (S) -Ty-Butyl 1- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenylamino) -1-oxo-3 Phenylpropane-2-ylcarbamate (1.0 g, 1.88 mmol) and trifluoroacetic acid (15 mL) were used to obtain a pale brown solid target compound (0.59 g, 1.37 mmol, 73%).

¹ H-NMR (400 MHz, DMSO _, δ) = 2.19 (s, 3H), 2.72 (t, 1H), 3.04 (t, 1H), 3.57 (q, 1H), 7.24 (m, 2H), 7.29 ( m, 4H), 7.40 (m, 2H), 7.77 (d, 1H), 7.95 (d, 1H), 8.06 (d, 1H), 8.54 (d, 1H), 9.12 (s, 1H), 9.82 (s , 1H)

Manufacturing example  19

Synthesis of thi-butyl 4- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenylcarbamoyl) phenylcarbamate

Similar to Preparation Example 1, N- (4- (pyridin-3-yl) pyrimidin-2-yl) benzene-1,4-diamine (1.90 g, 7.22 mmol) and 4- (thi-butoxycarbonylamino ) Benzoic acid (2.06 g, 8.67 mmol) was dissolved in dimethylformimide (50 mL), cooled to 0-5 ^o C, diethylcyanophosphonate (2.37 g, 14.44 mmol), triethylamine (2.19 g, 21.66 mmol) was used to obtain a pale yellow solid target compound (1.01 g, 2.10 mmol, 29.1%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.38 (s, 9H), 6.76 (d, 1H), 7.15 (m, 3H), 7.46 (d, 1H), 7.59 (m, 1H), 7.75 ( m, 4H), 8.50 (dd, 1H), 8.58 (d, 1H), 8.73 (d, 1H), 9.35 (s, 1H), 9.73 (s, 1H), 9.86 (s, 1H), 10.03 (s , 1H)

Manufacturing example  20

Synthesis of 4-amino-N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benzamide

Similar to Preparation 2, thi-butyl 4- (4- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenylcarbamoyl) phenylcarbamate (0.50 g, 1.04 mmol) was converted to trifluoro. Acetic acid (10 mL) was used to obtain a pale yellow solid target compound (0.32 g, 0.85 mmol, 81.5%).

¹ H-NMR (400 MHz, DMSO _, δ) = 5.32 (s, 2H), 6.76 (d, 1H), 7.15 (m, 3H), 7.46 (d, 1H), 7.58 (m, 1H), 7.74 ( m, 4H), 8.50 (dd, 1H), 8.58 (d, 1H), 8.73 (d, 1H), 9.33 (s, 1H), 9.72 (s, 1H), 10.01 (s, 1H)

Manufacturing example  21

Synthesis of 2-chloro-N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) acetamide

N- (4- (pyridin-3-yl) pyrimidin-2-yl) benzene-1,4-diamine (3.00 g, 11.39 mmol) was dissolved in dichloromethane (80 mL), followed by 2-chloroacetic acid (1.29 g). , 13.67 mmol), and 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCl, 2.62 g, 13.67 mmol) were added thereto, followed by stirring at room temperature for 3 hours. After the reaction was completed, the organic layer was washed with 1N aqueous hydrochloric acid solution (80 mL), saturated sodium bicarbonate (80 mL), saturated sodium chloride (80 mL), and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a pale yellow solid target compound (2.20 g, 6.48 mmol, 56.9%).

¹ H-NMR (400 MHz, DMSO _, δ) = 4.12 (s, 2H), 7.46 (d, 1H), 7.59 (m, 3H), 7.75 (d, 2H), 8.50 (m, 1H), 8.58 ( d, 1H), 8.70 (d, 1H), 9.33 (s, 1H), 9.63 (s, 1H), 9.70 (s, 1H)

Manufacturing example  22

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) acetamide

2-chloro-N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) acetamide (1.00 g, 2.94 mmol) was dissolved in dimethylformimide (20 mL). Triethylamine (0.60 g, 5.88 mmol) and 4-aminopiperidine (0.59 g, 5.88 mmol) were added and stirred for 8 hours. The organic layer was separated using ethyl acetate (80 mL) and saturated sodium chloride (50 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow solid target compound (0.60 g 1.49 mmol, 50.6%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.82 (m, 2H), 1.96 (m, 2H), 2.46 (m, 2H), 2.64 (m, 2H), 3.19 (s, 2H), 4.31 ( m, 1H), 4.83 (s, 2H), 7.46 (d, 1H), 7.59 (m, 3H), 7.75 (d, 2H), 8.50 (m, 1H), 8.58 (d, 1H), 8.70 (d , 1H), 9.33 (s, 1H), 9.63 (s, 1H), 9.70 (s, 1H)

Manufacturing example  23

Synthesis of 4- (chloromethyl) -N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benzamide

Similar to Preparation 21, N- (4- (pyridin-3-yl) pyrimidin-2-yl) benzene-1,4-diamine (5.00 g, 18.99 mmol) was dissolved in dichloromethane (100 mL), and 4 -(Chloromethyl) benzoic acid (3.89g, 22.79mmol), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCl, 4.37g, 22.79mmol) to pale yellow target compound (7.10 g, 17.07 mmol, 89.9%).

¹ H-NMR (400 MHz, DMSO _, δ) = 4.81 (s, 2H), 7.50 (m, 3H) 7.66 (m, 1H), 7.79 (d, 2H), 7.81 (d, 2H), 8.00 (m , 2H), 8.55 (m, 1H), 8.62 (d, 1H), 8.79 (m, 1H), 9.41 (d, 1H), 9.80 (s, 1H), 10.22 (s, 1H)

Preparation Example 24

4-((4- (2-aminoethyl) piperazin-1-yl) methyl) -N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benzamide synthesis

Similar to Preparation 22, 4- (chloromethyl) -N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benzamide (1.00 g, 2.40 mmol) was added to dimethylform. After dissolving in imide (20 mL), triethylamine (0.50 g, 4.81 mmol) and N- (2-aminoethyl) piperazine (0.62 g, 4.81 mmol) were used to give a pale yellow solid target compound (0.51 g, 0.98 mmol, 41.0%).

¹ H-NMR (400 MHz, DMSO _, δ) = 2.27 (m, 2H) 2.39 (m, 8H), 2.58 (m, 2H), 3.53 (s, 2H), 4.93 (s, 2H), 7.50 (m , 3H) 7.66 (m, 1H), 7.76 (d, 2H), 7.80 (d, 2H), 8.00 (m, 2H), 8.53 (m, 1H), 8.60 (d, 1H), 8.78 (m, 1H ), 9.40 (d, 1H), 9.78 (s, 1H), 10.20 (s, 1H)

Preparation Example 25

Synthesis of 4-((4-aminopiperidin-1-yl) methyl) -N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benzamide

Similar to Preparation 22, 4- (chloromethyl) -N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benzamide (1.00 g, 2.40 mmol) was added to dimethylform. After dissolving in imide (20mL), using triethylamine (0.50g, 4.81mmol) and 4-aminopiperidine (0.48g, 4.81mmol), pale yellow solid target compound (0.50g, 0.98mmol, 41.0 %) Was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 1.80 (m, 2H), 1.94 (m, 2H), 2.42 (m, 2H), 2.60 (m, 2H), 3.62 (s, 2H), 4.31 ( m, 1H), 4.90 (s, 2H), 7.46 (m, 3H), 7.59 (m, 1H), 7.74 (m, 4H), 7.99 (d, 2H), 8.54 (m, 1H), 8.62 (d , 1H), 8.79 (d, 1H), 9.39 (s, 1H), 9.70 (s, 1H), 10.11 (s, 1H)

Preparation Example 26

Synthesis of 2-chloro-N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) acetamide

Similar to Preparation 21, N- (4- (pyrazin-2-yl) pyrimidin-2-yl) benzene-1,4-diamine (3.00 g, 11.35 mmol) was dissolved in dichloromethane (80 mL), and then 2 Light yellow solid target compound (2.00) using chloroacetic acid (1.29 g, 13.62 mmol) and 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCl, 2.62 g, 13.62 mmol) g, 5.87 mmol, 51.7%).

¹ H-NMR (400 MHz, DMSO _, δ) = 3.89 (s, 2H), 7.59 (m, 3H), 7.75 (d, 2H), 8.65 (d, 1H), 8.80 (m, 2H), 9.51 ( s, 1H), 9.63 (s, 1H), 9.78 (s, 1H)

Preparation Example 27

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) acetamide

Similar to Preparation 22, 2-chloro-N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) acetamide (1.00 g, 2.93 mmol) was added to dimethylformimide ( 20 mL), and triethylamine (0.59 g, 5.87 mmol) and 4-aminopiperidine (0.59 g, 5.87 mmol) were used to give a pale yellow solid target compound (0.50 g, 1.24 mmol, 42.2%). Got it.

¹ H-NMR (400 MHz, DMSO _, δ) = 1.82 (m, 2H), 1.97 (m, 2H), 2.47 (m, 2H), 2.64 (m, 2H), 3.19 (s, 2H), 4.31 ( m, 1H), 4.83 (s, 2H), 7.59 (m, 3H), 7.75 (d, 2H), 8.64 (d, 1H), 8.79 (m, 2H), 9.50 (s, 1H), 9.63 (s , 1H), 9.77 (s, 1H)

Preparation Example 28

Synthesis of 4- (chloromethyl) -N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) benzamide

Similar to Preparation 21, N- (4- (pyrazin-2-yl) pyrimidin-2-yl) benzene-1,4-diamine (5.00 g, 18.92 mmol) was dissolved in dichloromethane (100 mL), and 4 Light yellow solid using (chloromethyl) benzoic acid (3.87 g, 22.70 mmol), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCl, 4.34 g, 22.70 mmol) Compound (6.80 g, 16.31 mmol, 86.2%) was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 4.68 (s, 2H), 7.45 (m, 2H) 7.66 (d, 1H), 7.79 (m, 4H), 7.93 (d, 2H), 8.68 (d , 1H), 8.90 (m, 2H), 9.55 (d, 1H), 9.85 (s, 1H), 10.18 (s, 1H)

Preparation Example 29

4-((4- (2-aminoethyl) piperazin-1-yl) methyl) -N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) benzamide synthesis

Similar to Preparation 22, 4- (chloromethyl) -N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) benzamide (1.00 g, 2.40 mmol) was added to dimethylform. After dissolving in imide (20 mL), using triethylamine (0.50 g, 4.81 mmol) and N- (2-aminoethyl) piperazine (0.62 g, 4.81 mmol), the pale yellow solid target compound (0.25 g, 0.49 mmol, 20.4%).

¹ H-NMR (400 MHz, DMSO _, δ) = 2.26 (m, 2H) 2.38 (m, 8H), 2.61 (m, 2H), 3.53 (s, 2H), 4.90 (s, 2H), 7.45 (m , 2H) 7.65 (d, 1H), 7.77 (m, 4H), 7.92 (d, 2H), 8.68 (d, 1H), 8.82 (m, 2H), 9.54 (d, 1H), 9.84 (s, 1H ), 10.17 (s, 1 H)

Preparation Example 30

Synthesis of 4-((4-aminopiperidin-1-yl) methyl) -N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) benzamide

Similar to Preparation 22, 4- (chloromethyl) -N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) benzamide (1.00 g, 2.40 mmol) was added to dimethylform. After dissolving in imide (20mL), using triethylamine (0.50g, 4.80mmol) and 4-aminopiperidine (0.48g, 4.80mmol), pale yellow solid target compound (0.55g, 1.17mmol, 47.7 %) Was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 1.77 (m, 2H), 1.94 (m, 2H), 2.38 (m, 2H), 2.60 (m, 2H), 3.62 (s, 2H), 4.31 ( m, 1H), 4.90 (s, 2H), 7.46 (m, 2H), 7.65 (d, 1H), 7.76 (m, 4H), 7.95 (d, 2H), 8.69 (d, 1H), 8.82 (m , 2H), 9.55 (s, 1H), 9.85 (s, 1H), 10.19 (s, 1H)

Preparation Example 31

Synthesis of 4- (chloromethyl) -N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) benzamide

Similar to Preparation 21, 6-methyl-N- (4- (thiazol-2-yl) pyrimidin-2-yl) benzene-1,3-diamine (5.00 g, 17.65 mmol) was added to dichloromethane (100 mL). After dissolving in 4- (chloromethyl) benzoic acid (3.61 g, 21.18 mmol) and 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCl, 4.02 g, 21.18 mmol) A light yellow solid target compound (6.25 g, 14.33 mmol, 81.2%) was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 2.26 (s, 3H), 4.80 (s, 2H), 7.38 (d, 1H) 7.45 (d, 1H), 7.62 (m, 3H), 7.94 (m , 1H), 7.96 (d, 2H), 8.06 (d, 1H), 8.16 (d, 1H), 8.53 (d, 1H), 9.07 (s, 1H), 10.23 (s, 1H)

Manufacturing example  32

4-((4-aminopiperidin-1-yl) methyl) -N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) benzamide Synthesis of

Similar to Preparation 22, 4- (chloromethyl) -N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) benzamide (1.00 g, 2.29 mmol) was dissolved in dimethylformimide (20 mL), followed by triethylamine (0.46 g, 4.59 mmol) and 4-aminopiperidine (0.46 g, 4.59 mmol) to give a pale yellow solid target compound (0.50 g). , 1.00 mmol, 43.7%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.74 (m, 2H), 1.92 (m, 2H), 2.24 (s, 3H), 2.33 (m, 2H), 2.52 (m, 2H), 3.55 ( s, 2H), 4.37 (m, 1H), 4.85 (m, 2H), 7.36 (d, 1H), 7.46 (m, 3H), 7.59 (m, 1H), 7.67 (m, 1H), 7.95 (m , 3H), 8.07 (d, 1H), 8.53 (d, 1H), 9.08 (s, 1H), 10.17 (s, 1H)

Manufacturing example  33

Synthesis of 2-chloro-N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) acetamide

Similar to Preparation 21, 6-methyl-N- (4- (pyridin-3-yl) pyrimidin-2-yl) benzene-1,3-diamine (3.00 g, 10.82 mmol) was added to dichloromethane (80 mL). After dissolving, pale yellow solid using 2-chloroacetic acid (1.23 g, 12.98 mmol) and 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCl, 2.47 g, 12.98 mmol) The desired compound (2.10 g, 5.94 mmol, 54.9%) was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 3.89 (s, 2H), 7.17 (d, 1H), 7.33 (m, 1H), 7.42 (d, 1H), 7.50 (s, 1H), 7.95 ( d, 1H), 8.43 (m, 1H), 8.52 (d, 1H), 8.70 (d, 1H), 8.96 (s, 1H), 9.26 (m, 1H), 9.68 (s, 1H)

Manufacturing example  34

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) acetamide

Similar to Preparation 22, 2-chloro-N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) acetamide (1.00 g, 2.83 mmol) was added to dimethyl. After dissolving in formimide (20 mL), triethylamine (0.57 g, 5.65 mmol) and 4-aminopiperidine (0.57 g, 5.65 mmol) were used to give a pale yellow solid target compound (0.48 g, 1.15 mmol, 40.6%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.81 (m, 2H), 1.96 (m, 2H), 2.21 (s, 3H), 2.46 (m, 2H), 2.64 (m, 2H), 3.16 ( s, 2H), 4.30 (m, 1H), 4.90 (s, 2H), 7.16 (d, 1H), 7.37 (m, 1H), 7.43 (d, 1H), 7.50 (m, 1H), 7.95 (d , 1H), 8.40 (m, 1H), 8.50 (d, 1H), 8.71 (m, 1H), 8.95 (s, 1H), 9.23 (m, 1H), 9.63 (s, 1H)

Manufacturing example  35

Synthesis of 4- (chloromethyl) -N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benzamide

Similar to Preparation 21, 6-methyl-N- (4- (pyridin-3-yl) pyrimidin-2-yl) benzene-1,3-diamine (5.00 g, 18.03 mmol) was added to dichloromethane (100 mL). After dissolution, the mixture was purified using 4- (chloromethyl) benzoic acid (3.69 g, 21.64 mmol) and 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCl, 4.11 g, 21.64 mmol). A yellow solid target compound (6.10 g, 14.19 mmol, 78.7%) was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 2.23 (s, 3H), 4.60 (s, 2H), 7.22 (d, 1H) 7.45 (m, 3H), 7.55 (m, 2H), 7.92 (d , 2H), 8.08 (d, 1H), 8.48 (m, 1H), 8.50 (d, 1H), 8.69 (m, 1H), 8.98 (s, 1H), 9.27 (m, 1H), 10.18 (s, 1H)

Manufacturing example  36

4-((4-aminopiperidin-1-yl) methyl) -N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benzamide synthesis

Similar to Preparation 22, 4- (chloromethyl) -N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benzamide (2.00 g, 4.65 mmol) ) Was dissolved in dimethylformimide (20 mL), and triethylamine (0.94 g, 9.30 mmol) and 4-aminopiperidine (0.93 g, 9.30 mmol) were used to give a pale yellow solid target compound (1.40 g, 2.84 mmol, 61.0%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.74 (m, 2H), 1.93 (m, 2H), 2.24 (s, 3H), 2.34 (m, 2H), 2.52 (m, 2H), 3.57 ( s, 2H), 4.40 (m, 1H), 4.89 (s, 2H), 7.22 (d, 1H) 7.45 (m, 3H), 7.55 (m, 2H), 7.92 (d, 2H), 8.08 (d, 1H), 8.48 (m, 1H), 8.50 (d, 1H), 8.69 (m, 1H), 8.98 (s, 1H), 9.27 (m, 1H), 10.18 (s, 1H)

Manufacturing example  37

Synthesis of 2-chloro-N- (4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) acetamide

Similar to Preparation 21, 6-methyl-N- (4- (pyrazin-2-yl) pyrimidin-2-yl) benzene-1,3-diamine (5.00 g, 17.97 mmol) was added to dichloromethane (80 mL). After dissolving, pale yellow solid using 2-chloroacetic acid (2.04 g, 21.56 mmol) and 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCl, 4.10 g, 21.56 mmol) The desired compound (3.15 g, 8.88 mmol, 49.4%) was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 2.22 (s, 3H), 3.89 (s, 2H), 7.17 (d, 1H), 7.35 (m, 1H), 7.60 (d, 1H), 8.00 ( s, 1H), 8.61 (d, 1H), 8.79 (m, 2H), 9.07 (s, 1H), 9.43 (m, 1H), 9.70 (s, 1H)

Manufacturing example  38

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) acetamide

Similar to Preparation 22, 2-chloro-N- (4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) acetamide (1.00 g, 2.82 mmol) was added to dimethyl. After dissolving in formimide (20 mL), triethylamine (0.57 g, 5.64 mmol) and 4-aminopiperidine (0.56 g, 5.64 mmol) were used to give a pale yellow solid target compound (0.52 g, 1.13 mmol, 38.5%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.81 (m, 2H), 1.97 (m, 2H), 2.20 (s, 3H), 2.47 (m, 2H), 2.64 (m, 2H), 3.14 ( s, 2H), 4.29 (m, 1H), 4.91 (m, 2H), 7.17 (d, 1H), 7.34 (m, 1H), 7.59 (d, 1H), 8.00 (s, 1H), 8.61 (d , 1H), 8.79 (m, 2H), 9.08 (s, 1H), 9.43 (m, 1H), 9.71 (s, 1H)

Manufacturing example  39

Synthesis of 4- (chloromethyl) -N- (4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) benzamide

Similar to Preparation 21, 6-methyl-N- (4- (pyrazin-2-yl) pyrimidin-2-yl) benzene-1,3-diamine (5.00 g, 17.97 mmol) was added to dichloromethane (100 mL). After dissolution, the mixture was diluted with 4- (chloromethyl) benzoic acid (3.68 g, 21.56 mmol) and 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCl, 4.13 g, 21.56 mmol). A yellow solid target compound (6.85 g, 15.90 mmol, 88.5%) was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 2.23 (s, 3H), 4.61 (s, 2H), 7.23 (d, 1H) 7.45 (m, 3H), 7.61 (m, 1H), 7.92 (d , 2H), 8.15 (s, 1H), 8.60 (m, 1H), 8.79 (m, 2H), 9.11 (s, 1H), 9.47 (m, 1H), 10.18 (s, 1H)

Manufacturing example  40

4-((4-aminopiperidin-1-yl) methyl) -N- (4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) benzamide synthesis

Similar to Preparation 22, 4- (chloromethyl) -N- (4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) benzamide (2.50 g, 5.80 mmol ) Was dissolved in dimethylformimide (20 mL), and then triethylamine (1.17 g, 11.60 mmol) and 4-aminopiperidine (1.60 g, 11.60 mmol) were used to give a pale yellow solid target compound (2.13 g, 4.31 mmol, 74.3%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.74 (m, 2H), 1.92 (m, 2H), 2.25 (s, 3H), 2.34 (m, 2H), 2.50 (m, 2H), 3.55 ( s, 2H), 4.40 (m, 1H), 4.92 (s, 2H), 7.22 (d, 1H) 7.44 (m, 3H), 7.61 (m, 1H), 7.92 (d, 2H), 8.15 (s, 1H), 8.61 (m, 1H), 8.79 (m, 2H), 9.10 (s, 1H), 9.47 (m, 1H), 10.17 (s, 1H)

Manufacturing example  41

Synthesis of 2-chloro-N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) acetamide

Similar to Preparation 21, 6-methyl-N- (4- (thiazol-2-yl) pyrimidin-2-yl) benzene-1,3-diamine (5.00 g, 17.65 mmol) was added to dichloromethane (80 mL). After dissolving in 2-chloroacetic acid (2.00g, 21.18mmol) and 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCl, 4.06g, 21.18mmol) Solid target compound (3.02 g, 8.39 mmol, 47.6%) was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 2.22 (s, 3H), 3.90 (s, 2H), 7.37 (m, 2H), 7.50 (m, 2H), 7.97 (d, 1H), 8.04 ( d, 1H), 8.56 (d, 1H), 9.07 (s, 1H), 9.63 (s, 1H)

Manufacturing example  42

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) acetamide

Similarly to Preparation 22, 2-chloro-N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) acetamide (1.00 g, 2.78 mmol) was added. After dissolving in dimethyl formumide (20 mL), triethylamine (0.56 g, 5.56 mmol) and 4-aminopiperidine (0.56 g, 5.56 mmol) were used to give a pale yellow solid target compound (0.46 g, 1.09 mmol). , 39.1%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.84 (m, 2H), 1.97 (m, 2H), 2.20 (s, 3H), 2.49 (m, 2H), 2.64 (m, 2H), 3.14 ( s, 2H), 4.35 (m, 1H), 4.90 (m, 2H), 7.37 (m, 2H), 7.50 (m, 2H), 7.99 (d, 1H), 8.07 (d, 1H), 8.56 (d , 1H), 9.09 (s, 1H), 9.64 (s, 1H)

Manufacturing example  43

Synthesis of thi-butyl 2-methyl-5- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenylcarbamoyl) phenylcarbamate

Similar to Preparation Example 6, 6-methyl-N- (4- (thiazol-2-yl) pyrimidin-2-yl) benzene-1,3-diamine (1.42 g, 5.00 mmol) and 3- (ti- Butoxycarbonylamino) -4-methylbenzoic acid (1.51 g, 6.00 mmol) was dissolved in dimethylformimide (50 mL), cooled to 0-5 ^° C., and diethylcyanophosphonate (1.64 g, 10.00 mmol). ), Triethylamine (1.52 g, 15.00 mmol) was used to obtain a pale yellow solid target compound (1.01 g, 1.96 mmol, 39.1%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.39 (s, 9H), 2.23 (s, 3H), 2.51 (s, 3H), 7.20 (d, 1H), 7.42 (d, 1H), 7.49 ( m, 1H), 7.56 (d, 1H), 7.86 (d, 1H), 7.92 (m, 3H), 8.06 (d, 1H), 8.58 (d, 1H), 9.18 (s, 1H), 9.73 (s , 1H), 10.21 (s, 1H)

Manufacturing example  44

Synthesis of 3-amino-4-methyl-N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) benzamide

Similar to Preparation Example 2, thi-butyl 2-methyl-5- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenylcarbamoyl) phenylcarbamate (1.01 g, 1.96 mmol) was used as trichloroacetic acid (20 mL) to obtain a pale yellow solid target compound (0.62 g, 1.49 mmol, 75.9%).

¹ H-NMR (400 MHz, DMSO _, δ) = 2.22 (s, 3H), 2.51 (s, 3H), 6.81 (m, 2H), 7.20 (d, 1H), 7.43 (d, 1H), 7.49 ( m, 1H), 7.56 (d, 1H), 7.86 (d, 1H), 7.93 (m, 3H), 8.06 (d, 1H), 8.59 (d, 1H), 9.18 (s, 1H), 10.21 (s , 1H)

Example  One

Synthesis of 4-isothiocyanato-N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) butanamide

Dissolve 4-amino-N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) butanamide (0.40 g, 1.10 mmol) in tetrahydrofuran (10 mL) After cooling to 0-5 ^o C, carbon disulfide (0.25 g, 3.30 mmol) and triethylamine (0.33 g, 3.30 mmol) were added, followed by stirring for 1 hour. 30% hydrogen peroxide solution (0.37 g, 3.30 mmol) was added thereto, followed by stirring for 3 hours. After the reaction was completed, the residue was purified by column chromatography to obtain a pale yellow solid target compound (0.29 g, 0.72 mmol, 65%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.96 (m, 2H), 2.20 (s, 3H), 2.44 (t, 2H), 3.76 (t, 2H), 7.15 (d, 1H), 7.29 ( dd, 1H), 7.73 (d, 1H), 7.54 (dd, 1H), 7.94 (d, 1H), 8.47 (tt, 1H), 8.70 (dd, 1H), 8.92 (s, 1H), 9.27 (dd , 1H), 9.94 (s, 2H)

IR _NCS = 2109 cm ^-1

Example  2

Synthesis of 4-isothiocyanato-N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) butanamide

Similar to Example 1 4-amino-N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) butanamide (0.5 g, 1.36 mmol), Light yellow solid target compound using carbon disulfide (0.31 g, 4.06 mmol), triethylamine (0.41 g, 4.06 mmol), 30% hydrogen peroxide solution (0.46 g, 4.06 mmol), tetrahydrofuran (10 mL), etc. (0.36 g, 0.87 mmol, 64%) was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 1.95 (m, 2H), 2.18 (s, 3H), 2.44 (t, 2H), 3.74 (t, 2H), 7.15 (d, 1H), 7.35 ( dd, 1H), 7.38 (d, 1H), 7.72 (d, 1H), 7.96 (d, 1H), 8.07 (d, 1H), 8.52 (d, 1H), 9.13 (s, 1H), 9.95 (s , 1H)

IR _NCS = 2107 cm ^-1

Example 3

Synthesis of N- (4- (isothiocyanatomethyl) phenyl) -4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) benzamide

Similar to Example 1 N- (4- (aminomethyl) phenyl) -4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) benzamide (0.70 g, 1.77 mmol), carbon disulfide Light yellow solid target compound (0.50g, 5.30mmol), triethylamine (0.54g, 5.30mmol), 30% hydrogen peroxide (0.6g, 5.30mmol), tetrahydrofuran (4mL) 1.13 mmol, 64%).

¹ H-NMR (400 MHz, DMSO _, δ) = 4.89 (s, 2H), 7.35 (d, 2H), 7.61 (m, 2H), 7.83 (d, 2H), 7.98 (s, 4H), 8.50 ( tt, 1H), 8.54 (tt, 1H), 8.69 (d, 1H), 8.75 (dd, 1H), 9.37 (d, 1H), 10.15 (s, 1H), 10.20 (s, 1H)

IR _NCS = 2084 cm ^-1

Example 4

Synthesis of N- (4- (isothiocyanatomethyl) phenyl) -4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) benzamide

Similar to Example 1 N- (4- (aminomethyl) phenyl) -4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) benzamide (0.60 g, 1.46 mmol ), Light yellow solid using carbon disulfide (0.33 g, 4.39 mmol), triethylamine (0.44 g, 4.39 mmol), 30% hydrogen peroxide (0.50 g, 4.39 mmol), tetrahydrofuran (11 mL) Compound (0.42 g, 0.93 mmol, 64%) was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 2.36 (s, 3H), 4.88 (s, 2H), 7.35 (d, 1H), 7.40 (d, 1H), 7.46 (d, 1H), 7.52 ( q, 1H), 7.72 (s, 1H), 7.83 (d, 2H), 8.26 (s, 1H), 8.46 (d, 1H), 8.54 (d, 1H), 8.69 (dd, 1H), 9.16 (s , 1H), 9.27 (d, 1H), 10.29 (s, 1H)

IR _NCS = 2085 cm ^-1

Example 5

Synthesis of (S) -2-isothiocyanato-N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) -3-phenylpropanamide

Similar to Example 1, (S) -2-amino-N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) -3-phenylpropanamide ( 0.70 g, 1.65 mmol), carbon disulfide (0.38 g, 4.95 mmol), triethylamine (0.50 mg, 4.95 mmol), 30% hydrogen peroxide (0.17 g, 4.95 mmol), tetrahydrofuran (13 mL) A light yellow solid target compound (0.52 g, 1.12 mmol, 68%) was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 2.29 (s, 3H), 3.11 (d, 2H), 4.77 (m, 1H), 6.47 (m, 1H), 7.07 (d, 1H), 7.19 ( m, 5H), 7.25 (d, 1H), 7.96 (d, 1H), 8.07 (m, 1H), 8.57 (d, 1H), 9.21 (s, 1H), 10.55 (s, 1H)

IR _NCS = 2028 cm ^-1

Example 6

Synthesis of N- (4-isothiocyanatophenyl) -4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) benzamide

Similar to Example 1 N- (4-aminophenyl) -4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) benzamide (0.30 g, 0.75 mmol), carbon Light yellow solid target compound (0.19) using disulfide (0.17 g, 2.26 mmol), triethylamine (0.23 g, 2.26 mmol), 30% hydrogen peroxide (0.26 g, 2.26 mmol), tetrahydrofuran (15 mL) g, 0.44 mmol, 58%).

¹ H-NMR (400 MHz, DMSO _, δ) = 2.39 (s, 3H), 6.53 (d, 2H), 7.33 (d, 1H), 7.42 (d, 2H), 7.64 (d, 1H), 7.77 ( d, 1H), 8.19 (s, 1H), 8.75 (d, 1H), 8.82 (s, 2H), 9.21 (s, 1H), 9.34 (s, 1H), 9.98 (s, 1H)

IR _NCS = 2017 cm ^-1

Example 7

Synthesis of N- (4- (isothiocyanatomethyl) phenyl) -4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) benzamide

Similar to Example 1 N- (4- (aminomethyl) phenyl) -4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) benzamide (0.6 g, 1.46 mmol ), A light yellow solid target compound using carbon disulfide (0.33 g, 4.38 mmol), triethylamine (0.44 g, 4.38 mmol), 30% hydrogen peroxide (0.50 g, 4.38 mmol), tetrahydrofuran (14 mL) (0.41 g, 0.91 mmol, 62%).

¹ H-NMR (400 MHz, DMSO _, δ) = 2.35 (s, 3H), 4.88 (d, 2H), 7.36 (d, 2H), 7.41 (d, 1H), 7.63 (d, 1H), 7.73 ( dd, 1H), 7.75 (d, 2H), 8.30 (d, 1H), 8.62 (d, 1H), 8.76 (s, 2H), 9.24 (s, 1H) 9.40 (s, 1H), 10.28 (s, 1H)

IR _NCS = 2087 cm ^-1

Example 8

Synthesis of N- (4- (isothiocyanatomethyl) phenyl) -4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) benzamide

Similar to Example 1 N- (4- (aminomethyl) phenyl) -4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) benzamide (0.60 g, 1.44 mmol), carbon disulfide (0.33 g, 4.32 mmol), triethylamine (0.43 g, 4.32 mmol), 30% hydrogen peroxide (0.49 g, 4.32 mmol), and pale yellow solid using tetrahydrofuran (14 mL). The desired compound (0.41 g, 0.91 mmol, 63%) was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 2.33 (s, 3H), 4.88 (d, 2H), 7.34 (d, 2H), 7.39 (s, 1H), 7.42 (d, 1H), 7.72 ( dd, 1H), 7.74 (d, 2H), 7.93 (d, 1H), 8.04 (d, 1H), 8.19 (d, 1H), 8.56 (d, 1H) 9.27 (s, 1H), 10.26 (s, 1H)

IR _NCS = 2088 cm ^-1

Example 9

Synthesis of (S) -2-isothiocyanato-N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) -3-phenylpropanamide

Similar to Example 1 (S) -2-amino-N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) -3-phenylpropanamide (0.50 g, 1.16 mmol), carbon disulfide (0.27 g, 3.48 mmol), triethylamine (0.35 g, 3.48 mmol), 30% hydrogen peroxide (0.35 g, 3.48 mmol), tetrahydrofuran (14 mL) To give a pale yellow solid target compound (0.30 g, 0.63 mmol, 54%).

¹ H-NMR (400 MHz, DMSO _, δ) = 2.27 (s, 3H), 3.17 (d, 1H), 4.12 (q, 1H), 4.77 (s, 1H), 6.48 (d, 1H), 7.07 ( s, 1H), 7.18 (m, 5H), 7.25 (d, 1H), 7.44 (d, 1H), 7.97 (d, 1H), 8.08 (d, 1H), 8.57 (d, 1H), 9.13 (s , 1H), 10.56 (s, 1H)

IR _NCS = 2013 cm ^-1

Example 10

Synthesis of 4-isothiocyanato-N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benzamide

Similar to Example 1 4-amino-N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benzamide (0.80 g, 2.09 mmol), carbon disulfide (0.48 g, 6.28 mmol), triethylamine (0.64 g, 6.28 mmol), 30% hydrogen peroxide (0.71 g, 6.28 mmol), tetrahydrofuran (16 mL), and pale yellow solid target compound (0.51 g, 1.17 mmol, 56.2%).

¹ H-NMR (400 MHz, DMSO _, δ) = 7.48 (d, 1H), 7.62 (m, 3H), 7.74 (m, 4H), 7.92 (d, 1H), 8.00 (s, 1H), 8.50 ( d, 1H), 8.59 (d, 1H), 8.72 (d, 1H), 9.33 (s, 1H), 9.77 (s, 1H), 10.28 (s, 1H)

IR _NCS = 2114 cm ^-1

Example  11

Synthesis of 2- (4-isothiocyanaepiperidine-1-yl) -N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) acetamide

Similar to Example 1 4-amino-N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benzamide (0.38 g, 0.94 mmol), carbon disulfide (0.22 g, 2.83 mmol), triethylamine (0.29 g, 2.83 mmol), hydrogen peroxide 30% (0.32 g, 2.83 mmol), tetrahydrofuran (16 mL), and pale yellow solid target compound (0.25 g, 0.56 mmol, 59.7%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.80 (m, 2H), 1.95 (m, 2H), 2.48 (m, 2H), 2.65 (m, 2H), 3.12 (s, 2H), 4.02 ( m, 1H), 7.46 (d, 1H), 7.59 (m, 3H), 7.74 (d, 2H), 8.47 (m, 1H), 8.57 (d, 1H), 8.72 (d, 1H), 9.31 (s , 1H), 9.61 (s, 1H), 9.69 (s, 1H)

IR _NCS = 2100 cm ^-1

Example  12

4-((4- (2-isothiocyanoethyl) piperazin-1-yl) methyl) -N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl Synthesis of Benzamide

Similar to Example 1 4-((4- (2-aminoethyl) piperazin-1-yl) methyl) -N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino ) Phenyl) benzamide (0.50 g, 0.98 mmol), carbon disulfide (0.22 g, 2.94 mmol), triethylamine (0.30 g, 2.94 mmol), 30% hydrogen peroxide (0.33 g, 2.94 mmol), tetrahydrofuran (10 mL) was used to obtain a light yellow solid target compound (0.16 g, 0.29 mmol, 29.6%).

¹ H-NMR (400 MHz, DMSO _, δ) = 2.53 (m, 8H) 2.63 (m, 2H), 3.68 (s, 2H), 3.76 (t, 2H), 7.49 (m, 3H) 7.60 (m, 1H), 7.72 (d, 2H), 7.79 (d, 2H), 7.95 (m, 2H), 8.50 (m, 1H), 8.60 (d, 1H), 8.74 (dd, 1H), 9.35 (d, 1H ), 9.75 (s, 1H), 10.17 (s, 1H)

IR _NCS = 2111 cm ^-1

Example  13

Synthesis of 4-((4-isothiocyanaepiperidine-1-yl) methyl) -N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benzamide

Similar to Example 1 4-((4-aminopiperidin-1-yl) methyl) -N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benz Amide (0.80 g, 1.67 mmol), carbon disulfide (0.38 g, 5.01 mmol), triethylamine (0.51 g, 5.01 mmol), 30% hydrogen peroxide (0.57 g, 5.01 mmol), tetrahydrofuran (10 mL) To give a pale yellow solid target compound (0.30 g, 0.57 mmol, 34.4%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.75 (m, 2H), 1.92 (m, 2H), 2.32 (m, 2H), 2.50 (m, 2H), 3.55 (s, 2H), 3.98 ( m, 1H), 7.44 (m, 3H), 7.60 (m, 1H), 7.75 (m, 4H), 7.92 (d, 2H), 8.50 (m, 1H), 8.60 (d, 1H), 8.73 (d , 1H), 9.35 (s, 1H), 9.75 (s, 1H), 10.16 (s, 1H)

IR _NCS = 2128 cm ^-1

Example  14

Synthesis of 2- (4-isothiocyanaepiperidine-1-yl) -N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) acetamide

Similar to Example 1 2- (4-aminopiperidin-1-yl) -N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) acetamide (0.5 g, 1.24 mmol), carbon disulfide (0.29 g, 3.71 mmol), triethylamine (0.38 g, 3.71 mmol), 30% hydrogen peroxide (0.42 g, 3.71 mmol), tetrahydrofuran (16 mL) A yellow solid target compound (0.20 g, 0.45 mmol, 36.1%) was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 1.83 (m, 2H), 1.97 (m, 2H), 2.49 (m, 2H), 2.65 (m, 2H), 3.13 (s, 2H), 4.02 ( m, 1H), 7.61 (m, 3H), 7.73 (d, 2H), 8.65 (d, 1H), 8.80 (m, 2H), 9.51 (s, 1H), 9.63 (s, 1H), 9.78 (s , 1H)

IR _NCS = 2100 cm ^-1

Example  15

4-((4- (2-isothiocyanatoethyl) piperazin-1-yl) methyl) -N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl Synthesis of Benzamide

Similar to Example 1 4-((4- (2-aminoethyl) piperazin-1-yl) methyl) -N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino ) Phenyl) benzamide (0.13 g, 0.26 mmol), carbon disulfide (0.06 g, 0.77 mmol), triethylamine (0.08 g, 0.77 mmol), 30% hydrogen peroxide (0.09 g, 0.77 mmol), tetrahydrofuran (10 mL) was used to obtain a pale yellow solid target compound (0.03 g, 0.05 mmol, 20.9%).

¹ H-NMR (400 MHz, DMSO _, δ) = 2.53 (m, 8H) 2.59 (t, 2H), 3.56 (s, 1H), 3.74 (t, 2H), 7.45 (d, 2H) 7.66 (d, 1H), 7.73 (d, 2H), 7.77 (d, 2H), 7.93 (m, 2H), 8.69 (d, 1H), 8.83 (m, 2H), 9.55 (d, 1H), 9.84 (s, 1H ), 10.17 (s, 1 H)

IR _NCS = 2099 cm ^-1

Example  16

Synthesis of 4-((4-isothiocyanaepiperidine-1-yl) methyl) -N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) benzamide

Similar to Example 1 4-((4-aminopiperidin-1-yl) methyl) -N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) benz Amide (0.27 g, 0.56 mmol), carbon disulfide (0.13 g, 1.69 mmol), triethylamine (0.17 g, 1.69 mmol), 30% hydrogen peroxide (0.19 g, 1.69 mmol), tetrahydrofuran (10 mL) To give a pale yellow solid compound (0.15 g, 0.29 mmol, 51.3%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.76 (m, 2H), 1.94 (m, 2H), 2.40 (m, 2H), 2.59 (m, 2H), 3.62 (s, 2H), 4.02 ( m, 1H), 7.46 (m, 2H), 7.65 (d, 1H), 7.76 (m, 4H), 7.95 (d, 2H), 8.68 (d, 1H), 8.82 (m, 2H), 9.54 (s , 1H), 9.84 (s, 1H), 10.18 (s, 1H)

IR _NCS = 2096 cm ^-1

Example  17

4-((4-isothiocyanaepiperidine-1-yl) methyl) -N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl Synthesis of Benzamide

Similar to Example 1 4-((4-aminopiperidin-1-yl) methyl) -N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-yl Amino) phenyl) benzamide (0.80 g, 1.60 mmol), carbon disulfide (0.37 g, 4.80 mmol), triethylamine (0.48 g, 4.80 mmol), 30% hydrogen peroxide (0.54 g, 4.80 mmol), tetrahydro Furan (10 mL) was used to obtain a light yellow solid target compound (0.13 g, 0.24 mmol, 15.0%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.74 (m, 2H), 1.92 (m, 2H), 2.25 (s, 3H), 2.33 (m, 2H), 2.51 (m, 2H), 3.57 ( s, 2H), 4.00 (m, 1H), 7.36 (d, 1H), 7.46 (m, 3H), 7.60 (m, 1H), 7.67 (m, 1H), 7.95 (m, 3H), 8.06 (d , 1H), 8.52 (d, 1H), 9.07 (s, 1H), 10.17 (s, 1H)

IR _NCS = 2084 cm ^-1

Example  18

2- (4-isothiocyanaepiperidine-1-yl) -N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) acetamide synthesis

Similar to Example 1 2- (4-aminopiperidin-1-yl) -N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) Acetamide (0.50 g, 1.20 mmol), carbon disulfide (0.27 g, 3.60 mmol), triethylamine (0.36 g, 3.60 mmol), 30% hydrogen peroxide (0.41 g, 3.60 mmol), tetrahydrofuran (16 mL) Using to obtain a pale yellow solid target compound (0.20g, 0.44mmol, 36.3%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.81 (m, 2H), 1.96 (m, 2H), 2.20 (s, 3H), 2.50 (m, 2H), 2.66 (m, 2H), 3.15 ( s, 2H), 4.00 (m, 1H), 7.16 (d, 1H), 7.35 (m, 1H), 7.43 (d, 1H), 7.51 (m, 1H), 7.95 (d, 1H), 8.44 (m , 1H), 8.51 (d, 1H), 8.71 (m, 1H), 8.95 (s, 1H), 9.26 (m, 1H), 9.67 (s, 1H)

IR _NCS = 2087 cm ^-1

Example  19

4-((4-isothiocyanaepiperidine-1-yl) methyl) -N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) Synthesis of Benzamide

Similar to Example 1 4-((4-aminopiperidin-1-yl) methyl) -N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino ) Phenyl) benzamide (1.40g, 2.84mmol), carbon disulfide (0.65g, 8.52mmol), triethylamine (0.86g, 8.52mmol), 30% hydrogen peroxide (0.97g, 8.52mmol), tetrahydrofuran (30mL) was used to obtain a light yellow solid target compound (0.62 g, 1.15 mmol, 40.5%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.75 (m, 2H), 1.94 (m, 2H), 2.23 (s, 3H), 2.34 (m, 2H), 2.52 (m, 2H), 3.56 ( s, 2H), 3.99 (m, 1H), 7.21 (d, 1H), 7.47 (m, 3H), 7.53 (m, 2H), 7.91 (d, 2H), 8.08 (d, 1H), 8.49 (m , 1H), 8.51 (d, 1H), 8.69 (dd, 1H), 8.99 (s, 1H), 9.28 (m, 1H), 10.17 (s, 1H)

IR _NCS = 2090 cm ^-1

Example  20

2- (4-isothiocyanaepiperidine-1-yl) -N- (4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) acetamide synthesis

Similar to Example 1 2- (4-aminopiperidin-1-yl) -N- (4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) Acetamide (0.65 g, 1.55 mmol), carbon disulfide (0.35 g, 4.65 mmol), triethylamine (0.46 g, 4.65 mmol), 30% hydrogen peroxide (0.53 g, 4.65 mmol), tetrahydrofuran (15 mL) Using to obtain a light yellow solid target compound (0.26g, 0.56mmol, 36.4%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.82 (m, 2H), 1.96 (m, 2H), 2.20 (s, 3H), 2.48 (m, 2H), 2.66 (m, 2H), 3.14 ( s, 2H), 3.99 (m, 1H), 7.18 (d, 1H), 7.36 (dd, 1H), 7.60 (d, 1H), 8.00 (s, 1H), 8.61 (d, 1H), 8.79 (m , 2H), 9.06 (s, 1H), 9.42 (d, 1H), 9.68 (s, 1H)

IR _NCS = 2099 cm ^-1

Example  21

4-((4-isothiocyanaepiperidine-1-yl) methyl) -N- (4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) Synthesis of Benzamide

Similar to Example 1 4-((4-aminopiperidin-1-yl) methyl) -N- (4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino ) Phenyl) benzamide (1.00g, 2.02mmol), carbon disulfide (0.46g, 6.07mmol), triethylamine (0.61g, 6.07mmol), 30% hydrogen peroxide (0.69g, 6.07mmol), tetrahydrofuran (30mL) was used to obtain a pale yellow solid target compound (0.63 g, 1.17 mmol, 58.7%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.75 (m, 2H), 1.91 (m, 2H), 2.24 (s, 3H), 2.32 (m, 2H), 2.50 (m, 2H), 3.17 ( s, 2H), 3.55 (s, 1H), 4.12 (m, 1H), 7.22 (d, 1H) 7.46 (m, 3H), 7.62 (d, 1H), 7.91 (d, 2H), 8.15 (s, 1H), 8.61 (m, 1H), 8.79 (s, 2H), 9.10 (s, 1H), 9.48 (m, 1H), 10.19 (s, 1H)

IR _NCS = 2131 cm ^-1

Example  22

2- (4-isothiocyanaepiperidine-1-yl) -N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) acetamide Synthesis of

Similar to Example 1 2- (4-aminopiperidin-1-yl) -N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl Acetamide (0.65 g, 1.53 mmol), carbon disulfide (0.35 g, 4.59 mmol), triethylamine (0.46 g, 4.59 mmol), 30% hydrogen peroxide (0.53 g, 4.59 mmol), tetrahydrofuran (15 mL) ) To give a pale yellow solid target compound (0.30g, 0.64mmol, 42.0%).

¹ H-NMR (400 MHz, DMSO _, δ) = 1.85 (m, 2H), 1.99 (m, 2H), 2.22 (s, 3H), 2.48 (m, 2H), 2.67 (m, 2H), 3.14 ( s, 2H), 4.00 (m, 1H), 7.37 (m, 2H), 7.50 (m, 2H), 7.95 (d, 1H), 8.06 (d, 1H), 8.51 (d, 1H), 9.03 (s , 1H), 9.64 (s, 1H)

IR _NCS = 2101 cm ^-1

Example  23

Synthesis of 3-isothiocyanato-4-methyl-N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) benzamide

Similar to Example 1 3-amino-4-methyl-N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) benzamide (0.64 g, 1.53 mmol), carbon disulfide (0.35 g, 4.59 mmol), triethylamine (0.46 g, 4.59 mmol), 30% hydrogen peroxide (0.53 g, 4.59 mmol), and tetrahydrofuran (15 mL). Solid target compound (0.35 g, 0.76 mmol, 49.9%) was obtained.

¹ H-NMR (400 MHz, DMSO _, δ) = 2.22 (s, 3H), 2.51 (s, 3H), 7.21 (d, 1H), 7.40 (d, 1H), 7.49 (m, 1H), 7.56 ( d, 1H), 7.86 (d, 1H), 7.92 (d, 1H), 7.95 (d, 1H), 7.97 (d, 1H), 8.05 (d, 1H), 8.54 (d, 1H), 9.17 (s , 1H), 10.21 (s, 1H)

IR _NCS = 2095 cm ^-1

Experimental Example  One : GFP  Reduction with expression influenza virus ( Reduction ) Assay

Influenza virus expressing GFP (Green fluorescence protein) was infected with cells for 1 hour, and then grown in medium to which different concentrations of compounds were added. After 24 to 72 hours, the GFP signal was observed using a fluorescence microscope. In addition, cells treated with no virus and compounds (Mock) and cells infected with only influenza virus were used as controls. If the compound has antiviral efficacy, the higher the concentration of the compound, the lower the GFP signal can be observed.

Experimental Example  2: plaque plaque ) formation On the unit  Due to reduction Assay

MDCK cells were infected with influenza virus at 200 plaque forming unit (PFU) / ml for 1 hour, and then the compounds were diluted in two steps and mixed in a medium containing 2% oxoid agar. Put it. Viruses not treated with the compound as a control were also infected with the cells. After incubation for 72 hours, staining with crystal violet was observed to form plaque. The plaque is a round shape that appears white because cells are not stained due to virus infection. The antiviral activity was analyzed by comparing the number of plaques or the size of the plaques with the concentration of the compound with the control group.

Experimental Example  3: plaque reduction In an assay  by Killer virus ( Virucidal ) Assay

This experiment is to determine whether the compound has the effect of inhibiting the invasion of the influenza virus by treating the compound directly with the virus before the virus is infected into the cell. To this end, compounds of different concentrations were first reacted with influenza virus at room temperature for 1 hour. After infecting the MDCK cells for 1 hour, the cells were washed with PBS, and then cultured with 2% oxoid agar. After 72 hours, the result was dyed with crystal violet and the plaque formation was observed. The antiviral activity was analyzed by comparing the number of plaques where the compound was added by concentration with the control.

Experimental Example  4 : GFP  With expressing influenza virus Killer virus ( Virucidal ) Assay

This experiment is to determine whether the compound has the effect of inhibiting the invasion of the influenza virus by treating the compound directly with the virus before the virus is infected into the cell. In this experiment, influenza virus expressing GFP and a compound of different concentrations were reacted with cells after 1 hour of reaction at room temperature. Antiviral activity was measured by measuring changes in intracellular GFP signals 24 hours after infection. In this experiment, the GFP signal was proportional to the concentration of the compound in cells treated with a compound that had antiviral activity on the hemagglutinin (HA) protein of the influenza virus, preventing the virus from entering the cell. It was confirmed that the decrease.

Experimental Example 5: MTT (3- (4,5-dimethylthiazol-2yl) -2,5-diphenyl-2H-tetrazolium bromide) Assay

This experiment is to determine the cytotoxicity of the compound (cytotoxicity). Different concentrations of compounds were added to the cells and treated for 24 hours. Thereafter, the MTT reagent was reacted for 1 hour. After 1 hour, the formazen crystal produced by MTT reagent was dissolved in DMSO, and the absorbance was measured by an ELISA reader.

Experimental Example  6: hemagglutinin ( Hemagglutination Inhibition Assay

This experiment is an experiment to confirm whether or not the compound of the present invention has an effect of inhibiting the function of the HA protein involved in cell adsorption of influenza virus. In general, the HA protein of the influenza virus binds to the red blood cells of the chicken, causing the red blood cells of the chicken not to fall to the bottom over time, resulting in hemagglutination. This experiment takes advantage of the property that a compound binds to the HA protein of influenza virus and prevents red blood cells from hemagglutination. The compound was reacted with the influenza virus for 1 hour, and then the red blood cells of the chicken were reacted to determine antiviral ability by hemagglutination of the red blood cells.

Experimental Example  7: Influenza Mini Replicon ( mini - replicon ) Assay

This experiment is to determine whether the compound affects the polymerase of influenza and inhibits the replication of viral genes. Plasmids containing GFP and polymerase complexes of influenza virus (RNP complex-PB2, PB1, PA, NP) were transformed into human cells. At this time, the cell culture medium containing different concentrations of the compound is put and cultured. While incubating for 24 to 48 hours, the GFP signal was observed by fluorescence microscopy. At this time, the compound was not used as a control.

Efficacy test for the antiviral of the compound prepared in the present invention was measured using the compounds of the Examples of the present specification using Experimental Examples 1 to 7, and confirmed that the chemical structure having the antiviral ability as a result It was.

Examples of compounds that prevent intracellular penetration of influenza virus among the example compounds of the present specification were confirmed by the viruci assay method and about 10 example compounds, and the compounds showing antiviral ability after the virus was infected intracellularly. The twelve example compounds were identified by the reduction assay. And the compound which showed positive reaction simultaneously by two assays was 10 Example compound. The results are shown in Table 1 below.

O = effective, X = no effective.

These compounds were subjected to MTT assay, reduction assay, and viruci assay to measure EC50, IC50, CC50, and SI (Selective index) values, and the results are shown in Table 2 below.

1) IC50 (Inhibitory Concentration 50%):

Measured by killer virus assay. Minimum concentration of compound that reduces by more than half the number of plaques in the control

2) EC50 (Effective Concentration 50%):

Measured by a reduction assay. Minimum concentration of compound that reduces by more than half the number of plaques in the control

3) CC50 (Cytotoxicity concentration 50%):

Measured by MTT Assay. Maximum concentration of compound that is reduced by more than half the number of cells in the control group

4) SI (Selective Index): Value expressed as CC50 / IC50 or CC50 / EC50

nd = not done

As can be seen from the results of Table 2, the SI value by IC50 and EC50 showed the SI value of the compound of Example 6 the best value. In addition, the compound of Example 22 showed a virucidal effect as a compound targeting a virus external protein (Hemagglutinin, HA), and the compound of Example 6 showed an effect on a virus targeting a viral polymerase. . In addition, most of the example compounds of the present specification showed excellent efficacy in targeting the virus internal proteins or host cells, that is, inhibiting the proliferation of infected viruses in cells. In particular, oseltamivir (tamiflu) and zanamivir (relenza), which are currently used as therapeutic agents for influenza virus, inhibit migration to cells not infected by inhibiting neuraminidase, which is involved in the release of influenza virus. It is a drug targeted to do so, and other therapeutic agents rely on influenza virus M2 ion channel inhibitors, amantadine and rimantadine. However, studies have now reported that resistant mutant influenza viruses are resistant to oseltamivir. This is because influenza viruses are RNA viruses that are easier to mutate than DNA. Therefore, with the emergence of resistant virus to oseltamivir and cases of adverse effects, the development of effective new influenza virus treatments is urgent.

Therefore, in Example 6, Example 22, and derivatives thereof, which are compounds showing antiviral effects by targeting a protein other than neuraminidase (NA) of influenza virus, which is a target of oseltamivir (Tamiflu, Tamiflu), Compounds are very useful drugs for the development of new effective influenza virus therapeutics.

Experimental Example 8

In rats  By oral administration Acute Toxicity Test

To confirm the acute toxicity of the compound according to the present invention was confirmed toxicity through oral administration in rats. Oral administration route was chosen because it is expected to be oral administration in the clinic. Six-week-old male rats (SD-Rat, 220 ± 30g) were supplied after quarantine temperature 22 ± 3 ℃, relative humidity 50 ± 20%, illumination 12 hr (08: 00 ~ 20: 00), illuminance 150 ~ 300 Lux A free period of feeding and watering was provided in the environment, with a period of one week of acclimation. The control group and the test group had 8 animals in each group, and the control group was orally administered with sonde according to the weight of each subject measured in concentrations of 0.5% HPMC and the test group suspended in 0.5% HPMC.

The doses of the drugs administered to the test group were set to three groups of 2000 mg / kg, single dose, 1000 mg / kg and 500 mg / kg of azeotropes in the nonclinical study. Body weight change was measured. The test animals that died during the test were examined and recorded for abnormalities of major organs (heart, liver, lung, spleen, kidney, colon), and on the 14th day after the last day of the test, all individuals were examined by the test substance. Changes in organs were observed compared to controls. In the control group, not only did the animals die, but no abnormalities occurred at necropsy.

Each group was orally administered at concentrations of 500 mg / Kg, 1000 mg / Kg, and 2000 mg / Kg, and the clinical symptoms were observed according to the test method for 14 days after the administration. Changes were visually observed. The control group, the 500 mg / Kg administration group, the 1000 mg / Kg administration group, and the 2000 mg / Kg administration group did not show any prognostic symptoms immediately after administration, and no deaths occurred in all dose administration groups. In addition, all the groups showed similar trends in body weight gain regardless of drug dose during the observation period, no adverse reactions were observed, and autopsy results did not show any peculiar findings. As a result of this experiment, the compounds of the examples illustrated in Table 3 were found to have an LD50 of 2000 mg / kg or more by oral administration. This result is to confirm that the compound of the present invention is a safe substance in terms of acute toxicity.

Claims (17)

A compound of Formula 1, or a hydrate, solvate, pharmaceutically acceptable salt, prodrug, complex, diastereomer or enantiomer thereof:

Formula 1
In the above formula
R1 represents thiazole, aminothiazole, imidazole, 2-methylimidazole, 4-methylimidazole, pyrazine, 2-methylpyrazine, or pyridine,
R2 represents H, lower alkyl or lower alkoxy,
R 3 or R 4 may be each independently substituted with a radical of Formula 2 or Formula 3,

Formula 2

Formula 3
Wherein R 5 represents a saturated or unsaturated monocyclic radical which optionally represents an aliphatic having 2 to 10 carbon atoms or contains 1 to 5 heteroatoms selected from nitrogen, oxygen, sulfur or halogen and contains 5 to 7 ring members or optionally A group in which the benzene ring represents a non- or tri-cyclic radical fused, or a ring member containing 3 to 10 carbon atoms and selected as lower alkyl, lower carbonyl, lower halo alkyl, independent halogen, or lower alkoxy as substituents; It represents a saturated or unsaturated ring radical containing, piperidinyl or piperazinyl, which may be substituted by lower alkyl, or phenyl radicals, which may be substituted by lower alkyl. The compound of claim 1, wherein when radicals of formula (2) or formula (3) are each substituted with R3, R2 and R4 each represent hydrogen, and when radicals of formula (2) or formula (3) are each substituted with R4, R2 represents methyl. R3 represents hydrogen. The method of claim 1,
R 1 represents pyrazine, pyridine, or thiazole,
When R3 is substituted with a radical of formula (2) or (3), respectively, R2 represents hydrogen or methyl, R4 represents hydrogen, R5 represents phenyl, 1-benzylpiperi substituted with methylpiperidine, phenyl or alkyl. Dine or a compound representing a 1-benzyl-4-ethylpiperazine group. The method of claim 1
R 1 represents pyrazine, pyridine, or thiazole,
When R4 is substituted with a radical of formula (2) or (3), respectively, R2 represents hydrogen or methyl, R3 represents hydrogen, R5 represents phenyl, 1-benzylpiperi substituted with methylpiperidine, phenyl or alkyl. Dine or a compound representing a 1-benzyl-4-ethylpiperazine group. The method of claim 1,
4-isothiocyanato-N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) butanamide,
4-isothiocyanato-N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) butanamide,
N- (4- (isothiocyanatomethyl) phenyl) -4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) benzamide,
N- (4- (isothiocyanatomethyl) phenyl) -4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) benzamide,
(S) -2-isothiocyanato-N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) -3-phenylpropanamide,
N- (4-isothiocyanatophenyl) -4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) benzamide,
N- (4- (isothiocyanatomethyl) phenyl) -4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) benzamide,
N- (4- (isothiocyanatomethyl) phenyl) -4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) benzamide,
(S) -2-isothiocyanato-N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) -3-phenylpropanamide,
4-isothiocyanato-N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benzamide,
2- (4-isothiocyanaepiperidine-1-yl) -N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) acetamide,
4-((4- (2-isothiocyanoethyl) piperazin-1-yl) methyl) -N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl Benzamide,
4-((4-isothiocyanaepiperidine-1-yl) methyl) -N- (4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) benzamide,
2- (4-isothiocyanaepiperidine-1-yl) -N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) acetamide,
4-((4- (2-isothiocyanatoethyl) piperazin-1-yl) methyl) -N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl Benzamide,
4-((4-isothiocyanaepiperidine-1-yl) methyl) -N- (4- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) benzamide,
4-((4-isothiocyanaepiperidine-1-yl) methyl) -N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl Benzamide,
2- (4-isothiocyanaepiperidine-1-yl) -N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) acetamide,
4-((4-isothiocyanaepiperidine-1-yl) methyl) -N- (4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl) Benzamide,
2- (4-isothiocyanaepiperidine-1-yl) -N- (4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) acetamide,
4-((4-isothiocyanaepiperidine-1-yl) methyl) -N- (4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) phenyl) Benzamide,
2- (4-isothiocyanaepiperidine-1-yl) -N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) acetamide , or
3-Isothiocyanato-4-methyl-N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) benzamide, or a hydrate thereof , Solvates, pharmaceutically acceptable salts, prodrugs, complexes, diastereomers or enantiomers. 2. The compound of claim 1, wherein N- (4-isothiocyanatophenyl) -4-methyl-3- (4- (pyrazin-2-yl) pyrimidin-2-ylamino) benzamide, or 2- ( 4-isothiocyanaepiperidine-1-yl) -N- (4-methyl-3- (4- (thiazol-2-yl) pyrimidin-2-ylamino) phenyl) acetamide, Or hydrates, solvates, pharmaceutically acceptable salts, prodrugs, complexes, diastereomers or enantiomers thereof. A first method comprising reacting a compound of Formula 4a or 4b with a compound of Formula 5 to produce a compound of Formula 6a or 6b, and leaving PG as a protecting group to generate a compound of Formula 7a or 7b. Process for preparing a compound of formula 1 as defined in claim:

Formula 4a

Formula 4b

Formula 5

Formula 6a

Formula 6b

Formula 7a

Formula 7b
Where
R1 to R5 are as defined in claim 1. Reacting the compound of Formula 4a or 4b with a compound of Formula 8 to produce a compound of Formula 9a or 9b, and reacting the compound with the compound of Formula 10 to form Compound 11a or 11b. A process for preparing a compound of formula 1 as defined in claim 1 comprising:

8

Formula 9a

Formula 9b

Formula 10

Formula 11a

Formula 11b
Wherein R 1 to R 5 are as defined in claim 1, R 6 represents phenyl substituted with lower alkyl or lower alkyl, X represents fluoro, chlorine, bromine or iodine, Y represents piperidine, piperazine, Or piperazine substituted with alkyl. Claim 1 comprising reacting a compound of formula 12a or 12b with a compound of formula 13 to produce a compound of formula 14a or 14b and leaving the protecting group PG to produce a compound of formula 15a or 15b Process for preparing a compound of formula 1 as defined in:

Formula 12a

Formula 12b

Formula 13

Formula 14a

Formula 14b

Formula 15a

Formula 15b
Wherein R1 to R5 are as defined in claim 1 and PG represents an amine protecting group. The process of claim 7, wherein the process of formula 1 is carried out in the presence of conventional solvents and / or acids or bases that do not adversely affect the reaction. The solvent according to claim 10, wherein the solvent is selected from the group consisting of tetrahydrofuran, methylene chloride, ethanol, N, N-dimethylformamide, N, N-dimethylacetamide, ethyl acetate, tert-butanol, toluene and dioxane. How to use more than one species. The compound of claim 10, wherein the base is pyridine, triethylamine, diethylamine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, sodium t- A method of using at least one selected from the group consisting of butoxide, potassium t-butoxide, lithium aluminum hydride, lithium borohydride, sodium nitrate and cesium carbonate. The method according to claim 10, wherein the acid is one or more selected from the group consisting of trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid, bromic acid, zinc bromide and acetic acid. A compound as defined in any one of claims 1 to 6, or a hydrate, solvate, pharmaceutically acceptable salt, prodrug, complex, diastereomer or enantiomer thereof, and a pharmaceutically acceptable carrier or A composition containing an excipient. A compound as defined in any one of claims 1 to 6, or a hydrate, solvate, pharmaceutically acceptable salt, prodrug, complex, diastereomer or enantiomer thereof, and a pharmaceutically acceptable carrier or A pharmaceutical composition for treating or preventing a viral infection containing an excipient. The composition of claim 15 used for oral use. The composition of claim 15 used for injection.