WO2005113550A1

WO2005113550A1 - Aminopyrimidine derivative and medicinal use thereof

Info

Publication number: WO2005113550A1
Application number: PCT/JP2005/009119
Authority: WO
Inventors: Hideo Tomozane; Ryoichi Ando; Shinsuke Oike
Original assignee: Mitsubishi Pharma Corporation
Priority date: 2004-05-20
Filing date: 2005-05-19
Publication date: 2005-12-01
Also published as: JPWO2005113550A1

Abstract

An aminopyrimidine compound represented by the following general formula (I), pharmaceutically acceptable salt, hydrate, water adduct, and solvate. These compounds were found to potently inhibit proteinkinases, especially aurora 2 kinase, and be capable of sufficiently acting in the living body. The invention has been thus completed. [Chemical formula 1]

Description

Specification

Aminovirimidine derivatives and their use as pharmaceuticals

Technical field

The present invention relates to a novel aminovirimidine conjugate and a drug containing the same as an active ingredient.

Background art

[0002] Protein kinases are known to be involved in signal transduction that controls cell activation, growth and division in response to extracellular mediators and environmental changes. In general, protein kinases are classified into two gnolops, serine Z-threonkinase and thymic synkinase, depending on their phosphorylation substrate.

[0003] It is known that abnormal activity of protein kinases causes a number of diseases accompanied by abnormal cell proliferation. Examples include hyperproliferative disorders such as cancer, tumors, hyperplasia, pulmonary fibrosis, angiogenesis, psoriasis, atheroma, intravascular smooth muscle proliferation such as stenosis or restenosis after angioplasty.

[0004] Here, malignant tumors are generated as a result of cancer cells undergoing cell control breakdown through multi-step genetic changes. Typical cancer cells have acquired an abnormally high proliferative capacity in addition to the ability to invade surrounding tissues and to metastasize to different organ sites. Loss of normal regulation of cell growth is precluded from generating abnormal forces in the signaling system that controls cell cycle progression.

[0005] In eukaryotes, the cell cycle is mainly controlled by the signal transduction pathway of the protein phosphorylation, and several protein kinases involved in this control have been identified.

[0006] One of these protein kinases is Aurora kinase. The Aurora kinase family is currently at least three related protein families. O Mouth lakinase is a highly conserved serine Z-threonine kinase, and is considered an important enzyme in the progression of the M phase because it is expressed in the M phase of the cell cycle. This key has also been demonstrated from inhibition of the function of the Aurora 2 kinase homologous gene using yeast, Drosophila and nematodes. The importance of the Nase family in the M phase was suggested (Non-Patent Document 1 and Non-Patent Document 2). Also, the fact that Aurora 2 kinase is overexpressed in many cancers (Non-patent Document 3, Non-patent Document 4, Non-patent Document 5, Non-patent Document 6, and Non-patent Document 7), Thus, the fact that cells overexpress Aurora 2 kinase showed signs of canceration became apparent (Non-Patent Document 8).

[0007] In addition, it has been shown that treatment of a human tumor cell line with an antisense oligonucleotide suppresses the expression of Aurora 2 kinase and suppresses cell proliferation (Patent Document 1). This suggests that inhibiting the activity of Aurora 2 kinase can suppress abnormal cell proliferation, and is considered to be useful for treating many diseases associated with abnormal cell proliferation, including cancer. Can be

[0008] Several small molecules that inhibit Aurora 2 kinase have been reported in patents and the like. For example, Patent Document 2, Patent Document 3, Patent Document 4, Patent Document 5, and Non-Patent Document 9 are mentioned.

[0009] In addition, aminoviridine-conjugated compounds having a thiazole ring at the 4-position are reported in the following patents and the like. For example, Patent Literature 6, Patent Literature 7, Patent Literature 8, Patent Literature 9, Patent Literature 10, and Non-Patent Literature 10 are mentioned, but there is no description about Aurora 2 kinase inhibitory activity.

Patent Document 1 JP 2002-95479A

Patent Document 2 WO2001--21595

Patent Document 3 WO2002--22601

Patent Document 4 WO2002--96905

Patent Document 5 WO2004--5283

Patent Document 6 W01997-19065

Patent Document 7 WO2001--72745

Patent Document 8 WO2002- -46170

Patent Document 9 WO2003-11838

Patent Document 10: WO2003-29249

Non-patent literature l: David M. Glover et al., Cell, 81, 95-105 1995

Non-Patent Document 2: Daniela Berdnik et al., Current Biology, 12 vol. 640-647 2002 Non-patent document 3: Hongyi Zhou et al., Nature Genetics ゝ 20 vol. 189-193 1998 Non-patent document 4: Takuji Tanaka et al., Cancer Research, 59 vol. 2041-2044 1999 Non-patent document 5: C. Sakakura et al. British Journal of Cancer, 84, 824-831 2001 Non-Patent Document 6: Subrata Sen et al., Journal of the National Cancer Institute, 94, 1320-1329 2002

Non-Patent Document 7: Donghui Li et al., Clinical Cancer Research, 9 Volume 991-997 2003 Non-Patent Document 8: James R. Bischol¾, EMBO Journal, 17 Volume 3052-3065 1998 Non-Patent Document 9: Elizabeth A. Harrington et al., Nature Medicine Advanced Online Publication, February 22, 2004

Non-Patent Document 10: Shudong Wang et al., Jounal of Medicinal Chemistry, 47 Vol. 1662-167, paragraph 5, 2004

Disclosure of the invention

Problems to be solved by the invention

[0010] There are several reports of substances that inhibit Aurora 2 kinase, but none of them have sufficient biological activity to treat diseases. An object of the present invention is to provide an Aurora 2 kinase inhibitor useful for treating cell proliferative diseases including cancer. Means for solving the problem

[0011] The present invention has been intensively studied in view of the powerful circumstances, and as a result, an aminobirimidine conjugate, a pharmaceutically acceptable salt, a hydrate, and a water adduct represented by the following general formula (I) Further, they have found that solvates are compounds that strongly inhibit protein kinases, particularly Aurora 2 kinase, and can sufficiently act in vivo, and have completed the present invention.

That is, the gist of the present invention is as follows.

(1) The following formula (I) [0013] [Formula 1]

[0014] wherein R ¹ and R ² are the same or different and represent a halogen atom, alkyl, hydroxy, alkoxy, aminoaminoalkylamino or acylamino,

R ³ and R ⁴ are the same or different and each represent a hydrogen atom, a halogen atom, alkyl, hydroxy or alkoxy;

R ⁵ represents a hydrogen atom, alkyl or acyl,

R ⁶ and R ⁷ may be the same or different and represent a hydrogen atom, a halogen atom, alkyl, hydroxy, alkoxy, alkylamino, acylamino, rubamoyl, alkylrubamoyl, carboxy, alkoxycarbonyl, sulfamoyl, alkylsulfamoyl, nitrite Show mouth or cyano,

R ⁸ is COR ^{^10,} CO R ^10, CONR

2 'V ¹ , CSNR ^ R ¹¹ , SOR ¹⁰ or OR ¹⁰

2

, R ^1C) and R ¹¹ may be the same or different from each other; —T—R ¹² (where T is absent or

1-6 Norequylene, c-Anoreckenylene, C-Anorecynylene or its anorecylene, anoreckenylene

2-6 2-6

Ren, alkyl - A C (= 0) to three methylene from one of Ren, one C (= 0) 0, one OC (= 0) -, one C (= 0諫¹⁴⁾ one, OC (= ^{0) N (R 14) -} , one NR ¹⁴ -, one ^{N (R 14) 0 -,} N (R 14) C (= 0) -, - N (R 14) C (= 0) 0 -, - N (R ¹⁴ ) C (= 0) N (R ¹⁵ ) —, S (0) —, NR

2

¹⁴ S (0) one, S (0) N (R 14) -, - N (R 14) C (NH) N (R 15) -, an oxygen atom or a sulfur atom

twenty two

(Wherein R ¹⁴ and R ¹⁵ are the same or different and represent hydrogen or alkyl), and R ¹² is hydrogen, a halogen atom, hydroxy, alkyl, alkyl having an amino group, Indicates a heterocycle or aryl. } Or R ^1C) and R ¹¹ represent a group that forms a 5- to 7-membered ring with the nitrogen atom bonded to each other. ],

R ⁹ represents a hydrogen atom, a force indicating alkyl, hydroxy, alkoxy or acyl.R ⁸ represents OR ¹⁰ , R ⁹ represents a hydrogen atom, or R ⁸ and R ⁹ each represent a group which forms a 5- to 7-membered ring together with a nitrogen atom bonded to each other. ], A pharmaceutically acceptable salt, hydrate, water adduct or solvate.

(2) In the above formula (I), R ³ and R ⁴ are the same or different and represent a hydrogen atom or an alkyl,

R ⁶ and R ⁷ are the same or different and represent a hydrogen atom, a halogen atom, an alkyl, a hydroxy or an alkoxy,

R ⁸ represents COR ¹⁰ , CONR′V ¹ , SOR ¹⁰ or OR ¹⁰ [wherein R ¹⁰ and R ¹¹ are the same or

2

Different from T—R ¹² {wherein T is absent, C alkylene or its alkylene

1-6

One one to three methylene of emissions C (= 0) -, one C (= 0) 0-, one C (= 0) N (R 14) -, - N (R 14) -, - N (R ¹⁴ ) C (= 0) — or one substituted with an oxygen atom. } Or, together with the nitrogen atom to which R ^1C> and R ¹¹ are mutually bonded, may further contain an oxygen atom, a sulfur atom, and a heteroatom whose NH force is also selected. In addition, it represents a group forming a 5- to 7-membered ring. ],

R ⁹ represents a hydrogen atom, an alkyl or acyl group, or

R ⁸ and R ⁹ each represent a group forming a 5- to 7-membered ring together with a nitrogen atom bonded to each other, the compound described in (1) above, a pharmaceutically acceptable salt, hydrate, water adduct or Solvate.

(3) In the formula (I), R ¹ and R ² are the same or different and each represents alkyl or acylamino. The compound according to the above (1) or (2), a pharmaceutically acceptable salt, hydrate, Water adduct or solvate.

(4) In the above formula (I), R ³ and R ⁴ each represent a hydrogen atom. (1) The compound according to any one of (1) to (3), a pharmaceutically acceptable salt, hydrate, water Adduct or solvate.

(5) In the above formula (I), R ⁵ represents a hydrogen atom, (1) the compound of any one of (3) above, a pharmaceutically acceptable salt, hydrate, water adduct or solvent Japanese food.

(6) In the above formula (I), R ³ and R ⁴ each represent a hydrogen atom, and R ⁵ represents a hydrogen atom. The compound according to any one of the above (1) to (5), which is pharmaceutically acceptable. Salts, hydrates, water adducts or solvates.

(7) It is characterized by containing the aminovirimidine conjugate represented by the above (1) to (6) or a pharmaceutically acceptable salt, hydrate, water adduct and solvate thereof. Cancer prevention and Z or therapeutic agent. The invention's effect

According to the present invention, the compound is selected from the group consisting of aminovirimidine conjugates represented by the general formula (I), pharmaceutically acceptable salts, hydrates, water adducts, and solvates. A therapeutic agent for cancer containing a substance as an active ingredient can be provided.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

[0017] Each substituent represented by the above general formula (I) of the present invention is defined below.

The “halogen atom” represented by R ¹ or R ² includes, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

“Alkyl” for R ¹ or R ² includes C 1 alkyl (eg, methyl, ethyl, propyl)

1-6

Mouth pill, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), and alkyl of C (eg, methyl, ethyl, propyl, isopropyl)

1-3

Particularly preferred is methyl.

“Alkoxy” for R ¹ or R ² includes, for example, C 1 alkoxy,

1-6

Specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy and the like, and preferably methoxy.

The “alkylamino” represented by R ¹ or R ² includes, for example, alkylamino of C 1

1-6

Specifically, methylaminoethylamine, n-propylamidoisopropylamino, n-butylaminiumdimethylamine, ethylamylamine N-methyl-N-ethylaminoamine, mouth lysine-1-yl, piperidine-1-yl And preferably dimethylamino with methylamino.

The “acylamino” represented by R ¹ or R ² includes, for example, C-acylamino

1-6

Specific examples include formylamido-acetylamido-propioluamido-butyrylamino, and preferably acetylamino.

The alkyl, alkoxy, alkylamino or acylamino represented by R ¹ or R ² may have a substituent. Here, as the substituent, for example, alkyl of C (eg, methyl

1-6

, Ethyl, etc.), halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), hydroxy, C alkoxy, oxo, carboxy, C alkoxycarbonyl (E.g., tert-butoxycarbol, etc.), acyl (e.g., formyl, etc.), acylyloxy, aminoalkylamino, dialkylamino, amide, alkylamide, carbamoyl, sulfalyl, anolequinolenosphenol Nole, Snolefuino, Anolequinoresnoreho-nore (eg, methinoresnoreho-nore, ethylsulfol and the like), sulfamoyl, alkylsulfamoyl and the like.

As the “nodogen atom” represented by R ³ or R ⁴ , those similar to the “halogen atom” represented by R ¹ or R ² can be mentioned.

The “alkyl” represented by R ³ or R ⁴ includes the same as the “alkyl” represented by R ¹ or R ² , and preferably includes methyl.

As the “alkoxy” represented by R ³ or R ⁴ , those similar to the “alkoxy” represented by R ¹ or R ² can be mentioned.

[0027] The alkyl or alkoxy represented by R ³ or R ⁴ has a substituent! /, Or! /. Here, examples of the substituent include those similar to the substituents represented by R ¹ or R ² .

The “alkyl” represented by R ⁵ is the same as the “alkyl” represented by R ¹ or R ² above, and preferably includes methyl.

[0029] As "Ashiru" represented by R ^5, for example, the number of carbon include Ashiru from 1 6, specifically formyl, Asechiru, propionitrile - methylphenol, 2 Mechirupuropio - le, butyryl and the like elevation up And preferably acetyl.

[0030] The alkyl or acyl represented by R ⁵ has a substituent! /, Or may be! /. Here, examples of the substituent include those similar to the substituents represented by R ¹ or R ² .

The “nodogen atom” represented by R ⁶ and R ⁷ is the same as the “halogen atom” represented by R ¹ or R ² , and is preferably a chlorine atom.

The “alkyl” represented by R ⁶ and R ⁷ is the same as the “alkyl” represented by R ¹ or R ² , and is preferably methyl.

The “alkoxy” represented by R ⁶ and R ⁷ includes the same as the “alkoxy” represented by R ¹ or R ² , and preferably includes methoxy.

As the “alkylamino” represented by R ⁶ and R ⁷ , the same as “alkylamino” represented by R ¹ or R ² can be mentioned, and preferably, dimethylamino with methylamine is exemplified. As the “acylamino” represented by R ⁶ and R ⁷ , those similar to the “acylamino” represented by R ¹ or R ² can be mentioned.

[0036] The "alkyl power rubamoyl" represented by R ⁶ and R ⁷ includes, for example, an alkyl power

1 -6

Lubamoyl, specifically, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, ethylmethylcarbamoyl, and the like.

[0037] The "alkoxycarbon" represented by R ⁶ and R ⁷ includes, for example,

1 -6

And specific examples thereof include methoxycarbol, ethoxycarbol, propoxycarbonyl, isopropoxycarbol, butoxycarbol, tertiary butoxycarbol, and the like.

The “alkylsulfamoyl” represented by R ⁶ and R ⁷ includes, for example, C alkyls

1 -6

Ruffamoyl, specifically, methylsulfamoyl, ethylsulfamoyl and the like.

[0039] represented by R ⁶ or R ^7, alkyl, alkoxy, Arukiruamino, Ashiruamino, alkylcarbamoyl, alkoxycarbonyl - le or alkylsulfamoyl may have a substituent. Here, examples of the substituent include those similar to the substituents represented by R ¹ or R ² .

The “alkyl” represented by R ^{9 includes the same} as the “alkyl” represented by R ¹ or R ² above, and preferably includes methyl.

As the “alkoxy” for R ⁹ , those similar to the “alkoxy” for R ¹ or R ² can be mentioned.

[0042] As "Ashiru" represented by R ^9, the ones similar to the "Ashiru" represented by R ⁴ is exemplified et al are preferably Asechiru include butyryl and Benzoiru.

Alkyl, alkoxy or acyl represented by R ⁹ has a substituent! /, Or may be! /. Here, examples of the substituent include those similar to the substituents represented by R ¹ or R ² .

R ⁸ and R ⁹ forces The group forming a 5- to 7-membered ring together with a nitrogen atom bonded to each other includes an oxygen atom, a sulfur atom and N—R ¹³ (R ¹³ is hydrogen Atom, alkyl, aralkyl or acyl).). Examples of the 5- to 7-membered ring include pyrrolidine, piperidine, piperazine, monoreforin, and thiomonorefurol. Thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, thiazole, and isooxazole. Further, the 5- to 7-membered ring may have a substituent. Here, examples of the substituent include those similar to the substituents represented by R ¹ or R ² , and also include an oxygen atom.

The group in which R ^1C> and R ¹¹ form a 5- to 7-membered ring together with a nitrogen atom bonded to each other includes a heteroatom selected from an oxygen atom, a sulfur atom, and a nitrogen atom in a 5- to 7-membered ring. May be included. Examples of the 5- to 7-membered ring include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, thiazole and isoxazole. The 5-membered or 7-membered ring may have a substituent. Here, examples of the substituent include the same substituents as those represented by R ¹ or.

As the “alkyl” for R ¹² , those similar to the “alkyl” for the above R ¹ or R ² can be mentioned, and preferred are C 1 alkyl, and specifically, methyl, The

1-4

Butyl, isopropyl, tert-butyl and trifluoroethyl.

[0047] As "Nono androgenic atom" represented by R ^12, the R ¹ or the same "Nono androgenic atom" represented by R ² can be mentioned, preferably a chlorine atom and a bromine atom.

“Cycloalkyl” for R ¹² includes, for example, C 1 cycloalkyl

3-8

Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, and preferred examples include cyclopropyl and cyclohexyl.

[0049] The "heterocycle" represented by R ¹² includes, for example, one or two hetero atoms selected from one or two selected from a nitrogen atom, a sulfur atom and an oxygen-nuclear atom, in addition to a carbon atom, And a 5- to 7-membered aromatic heterocyclic ring or non-aromatic heterocyclic ring. Specific examples include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiophene, furan, pyrrole, imidazole, and pyrazole. And pyridine, pyrazine, pyrimidine, thiazole and isoxazole, preferably piperazine, piperidine, morpholine, homopidazine, thiophene, pyridine and thiazole.

The “aryl” represented by R ¹² includes a single ring or a condensed ring, and includes, for example, phenyl, 1-naphthyl, 2-naphthyl and the like, and preferably includes phenyl. [0051] alkyl represented by R ^12, Ami input cycloalkyl, heterocyclic or Ariru may optionally have a substituent. Here, examples of the substituent include those similar to the substituents represented by R ¹ or R ² , and in addition, a heterocyclic ring (eg, 4-methylbiperazinomethyl, morpholinomethyl, etc.) and the like. No.

As the “alkyl” for R ¹³ , those similar to the “alkyl” for R ¹ or R ² can be mentioned.

“Aralkyl” represented by R ¹³ includes, for example, C aralkyl.

7- 16

Typical examples include benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl and the like.

[0054] As "Ashiru" represented by R ¹³ are the like et be the same "Ashiru" represented by R ^4.

[0055] represented by R ^13, alkyl, Ararukiru or Ashiru is substituted! /, Even I! /,. Here, examples of the substituent include those similar to the substituents represented by R ¹ or R ² .

As “alkyl” represented by R ¹⁴ and R ¹⁵ , the same as “alkyl” represented by R ¹ or R ² can be mentioned.

The alkyl represented by R ¹⁴ and R ¹⁵ may have a substituent. Here, examples of the substituent include those similar to the substituents represented by R ¹ or R ² .

[0058] Specific examples of the compound of the present invention include, for example, the following compounds.

[0059] Table 1

[Formula 2]

Chemical 3]

Chemical 4]

Chemical 5]

Chemical 6]

Yidani 7]

8

[0067] [Formula 9]

[0068] The pharmaceutically acceptable salt of the compound of the general formula (I) of the present invention includes an acid addition salt with an inorganic acid or an organic acid.

[0069] Further, since the compound of the present invention may exist as a water adduct, hydrate and solvate, these water adducts, hydrates and solvates are also included in the present invention. Is done.

[0070] The compound of the general formula (I) of the present invention can be produced by the method described below.

In the following general formulas, unless otherwise specified, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁹ is as defined above. Is as

[0072]

[0073] 1. Reaction 1

The compound represented by the above general formula (IV) (Shudong Wang et al., Jounal of Medicinal Chemistry, Vol. 47, pp. 1662-1675, 2004) is prepared under appropriate reducing conditions, that is, in the presence of a catalyst such as iron. In a suitable acid (e.g., acetic acid or hydrochloric acid) and a suitable solvent (e.g., ethanol, dioxane, water, or a mixture thereof) under the conditions of 60 ° C to 100 ° C. By reacting for 5 to 6 hours, the compound of the above general formula (ΠΙ) can be produced.

The compound represented by the above general formula (III) is represented by X—R ⁹ ′ (wherein, R ⁹ ′ represents a group excluding the R ⁹ hydrogen atom, hydroxy or alkoxy group defined above, and X represents Reacting with a halogen atom or a good leaving group) to produce a compound represented by the above general formula (Π) (wherein R ⁹ is other than a hydrogen atom, hydroxy or alkoxy). Can be.

Further, the compound represented by the above general formula (III) and R ¹⁶ —CO—R ¹⁷ (wherein, R ¹⁶ and R ¹⁷ may be the same or different and may have an appropriate substituent After reacting an alkyl group or one of which represents a hydrogen atom), hydrogen is added to form a compound represented by the above general formula (Π) (wherein, R ⁹ represents other than a hydrogen atom, hydroxy or alkoxy). Can be produced. 2.Reaction 2

The compound represented by the above general formula (IV) is subjected to a hydrogen addition reaction in the presence of palladium-carbon (Pd-C), and a suitable solvent (for example, methanol, ethanol, water or any mixture thereof) is added. Solvent, etc.) at room temperature for 1 hour to 12 hours to produce a compound represented by the above general formula (Π) (wherein R ⁹ represents a hydrogen atom, hydroxy or alkoxy) be able to.

Further, the compound represented by the above general formula (Π) is converted to X—COR ¹⁰ , X-CO R ¹⁰ , R ¹⁰ -NC

2

0, R ^1G — NCS or X—SO R ^1G (R ^1G is as described above, X is a halogen atom, hydroxy

2

Shows a good or good leaving group. The compound represented by the general formula (I) (wherein R) can be obtained by reacting any of the compounds of the formula (I) or, in some cases, further reacting with a generally used alkylating agent. ⁸ is COR CO R ¹⁰ , CONR

2 'V ¹ , CSN

RR ¹¹ or SOR ¹⁰ ) can be produced.

2

[0077] In addition, the compound represented by the above general formula (IV) is subjected to a hydrogenation reaction in the presence of palladium-carbon (Pd-C), and a suitable solvent (for example, ethanol, ethanol, water or a mixture thereof). In an arbitrary mixed solvent, etc.) at room temperature for 1 hour to 12 hours to obtain a compound represented by the following general formula (la) wherein R ⁸ in the general formula (I) represents OR

[0078] [Formula 11]

(Wherein RR ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ′ or R ^1C) are as described above ⁾ .

Further, when applicable in each of the above synthesis steps, each compound can be derived and converted to another compound using a method well known in the art.

[0081] In each of the above synthesis steps, protection or deprotection of a functional group is sometimes required. A suitable protecting group can be selected depending on the type of the functional group, and a method well known in the art may be applied. [0082] The salt of a cyanopyridine derivative represented by the general formula (I), or a hydrate or solvate thereof, can be produced by a method having a known cyanopyridine derivative power.

[0083] The compound of the general formula (I) obtained by the above method, or a pharmaceutically acceptable salt, carohydrate with water, hydrate and solvate thereof has a strong Aurora 2 kinase inhibitory action, It is useful as a cancer prevention and Z or therapeutic agent.

[0084] The method of administration when the compound of the present invention is used as a medicament can be appropriately selected by those skilled in the art. For example, parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection or the like, or a different administration route of oral administration can be selected. The dose can be appropriately determined depending on conditions such as the age, health condition, and body weight of the patient, the type and frequency of administration of a drug to be administered at the same time, if any, or the nature of the desired effect. Generally, the daily dose of the active ingredient is 0.5 to 300 mgZkg body weight, usually 1 to 30 mgZkg body weight, and it can be administered once or more per day.

[0085] When the compound of the present invention is used as a medicament, it is preferable to prepare and administer a pharmaceutical composition containing the above active ingredient and one or more kinds of pharmaceutical additives.

[0086] Pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, powders, liquids, and elixirs. Pharmaceutical compositions suitable for parenteral administration include, for example, liquids Alternatively, a sterilized liquid pharmaceutical composition such as a suspending agent can be exemplified.

[0087] The type of the pharmaceutical additive used for preparing the pharmaceutical composition is not particularly limited, and an appropriate pharmaceutical additive can be selected according to the form of the various pharmaceutical compositions. As an additive for pharmaceutical preparations, a solid or liquid carrier, for example, a solid carrier or a liquid carrier can be used. As an example of the solid carrier, a usual gelatin type capsule can be used. In addition, for example, the active ingredient can be tableted with or without one or more pharmaceutical additives, or can be prepared as a powder and packaged. These capsules, tablets and powders may generally contain from 5 to 95% by weight, preferably from 5 to 90% by weight, of the active ingredient, based on the total weight of the formulation, the dosage unit form being from 5 to 500 mg, It preferably contains 25 to 250 mg of the active ingredient. Liquid carriers include water, petroleum, peanut oil, soybean oil, mineral oil, sesame oil, etc. Or an oil of animal or plant origin or a synthetic oil.

[0088] In general, physiological saline, dextrol or a similar sucrose solution, and glycols such as ethylene daricol, propylene glycol, and polyethylene glycol are preferred as liquid carriers. In that case, it can be usually prepared to contain 0.5 to 20%, preferably 1 to 10% by weight of the active ingredient.

Example

[0089] Hereinafter, the present invention will be described more specifically with reference to Production Examples, Examples, and Pharmacological Experimental Examples, but the present invention is not limited to these descriptions. Note that 1H-NMR was measured at 300 MHz or 400 MHz using DMSO-d6 as a solvent unless otherwise specified. 1H-NMR chemical shift values were expressed in relative delta (δ) values in parts per million (ppm) using tetramethylsilane (TMS) as an internal standard. Coupling constants indicate trivial multiplicity in Hertz (Hz), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (double doublet), brs (Broad singlet) etc. Column chromatography was performed using silica gel manufactured by Merck or Fuji Silicia Chemical.

[0090] Production Example 13-Trofu-leguadin

To a solution of 3-troin-phosphorus (20.0 g, 0.15 mol) and cyanamide (10.7 g) in 1,4-dioxane (150 ml) was added 4N hydrochloric acid Z1,4 dioxane solution (63 ml) under ice-cooling, and the mixture was heated to 80 ° C. For 4 hours. A 6N aqueous sodium hydroxide solution (50.7 ml) was added to the reaction mixture under ice cooling, and then 1,4 dioxane was distilled off under reduced pressure. The deposited precipitate was collected by filtration, washed with water, and dried under reduced pressure at 60 ° C. to obtain 3-trophyrazine (23.8 g, 91%).

1H-NMR: 7.60 (1H, m), 7.52 (1H, brs), 7.39 (1H, dd, 8Hz, 8Hz), 7.16 (1H, d, J = 8Hz), 5.41 (4H, brs).

Production Example 2 3 Dimethylamino-1 (2,4 dimethylthiazole-5-yl) propionone

5-Acetyl-1,2 dimethylthiazole (20.0 g, 0.13 mol) was dissolved in ethanol (85 ml), and N, N-dimethylformamide dimethyl acetal (85.6 ml) was heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and getyl ether was added to the residue. By filtration, 3-dimethylamino-11- (2,4-dimethylthiazol-5-yl) propenone (18.9 g, 70%) was obtained.

1H-NMR: 7.64 (1H, d, J = 12 Hz), 5.32 (1H, d, J = 12 Hz), 3.13 (3H, brs), 2.58 (3H, brs), 2.58 (3H, s), 2.55 (3H , s).

Production Example 3 (4— (2,4 dimethylthiazol-5-yl) pyrimidine-2-yl)-(3

-Trofu-er) Amin

3 Dimethylamino-11 (2,4 dimethylthiazole-5-yl) probenone (20.0 g, 0.095 mol) and 3-trophenol-arginine (18.8 g) in 2-methoxyethanol (400 ml) Heated to reflux for hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration to give (4- (2,4-dimethylthiazol-5-yl) pyrimidin-1-yl) (3 -Trophele) amine (22.5 g, 72%) was obtained.

1H-NMR: 10.20 (1H, s), 8.92 (1H, m), 8.61 (1H, d, J = 5 Hz), 8.08 (1H, m), 7.82 (1H, m), 7.59 (1H, dd, J = 8Hz, 8Hz), 7.20 (1H, d, J = 5Hz), 2.67 (3H, s), 2.66 (3H, s).

Production Example 4 N— (4- (2,4 dimethylthiazol-5-yl) pyrimidine-2-yl) benzene 1,3 diamine

A suspension of iron powder (8.5 g) in acetic acid (50 ml) was stirred at 60 ° C for 30 minutes, and then water (150 ml) and (4- (2,4 dimethylthiazol-5-yl) pyrimidine-2-y A solution of 1,4-dioxane (10.0 g, 30.5 mmol) in 1,4-dioxane (500 ml) was stirred at 60 ° C. for 1 hour. After cooling, the reaction solution was filtered, the filtrate was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated crystals were collected by filtration to give N- (4- (2,4-dimethylthiazol-5-yl) pyrimidine-2-yl) benzene-1, 3-diamine (8.2 g, 90% ).

1H-NMR: 9.31 (1H, s), 8.47 (1H, d, J = 5 Hz), 7.01 (2H, m), 6.92 (2H, m), 6.22 (1H, m), 4.92 (2H, s), 2.65 (3H, s), 2.63 (3H, s).

Example 1 Compound 1 in Table 1

N, N dimethyl of (4- (2,4 dimethylthiazol-5-yl) pyrimidine-2-yl)-(3 ditrophenyl) amine (5.00 g, 15.3 mmol) obtained in Production Example 3 Holmwa 10% palladium carbon (0.50 g) was added to the amide (100 ml) solution, and the mixture was stirred at room temperature under a hydrogen gas atmosphere for 6 hours 30 minutes. The reaction solution was filtered, water was added to the filtrate, extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate and n-hexane were added to the residue, and the precipitated crystals were collected by filtration to give N- (3- (4- (2,4 dimethylthiazol-5-yl) pyrimidine-2--2-ylamino) phenyl) hydroxyl. Amine (2.05 g, 43%) was obtained. 1H-NMR: 9.48 (1H, s), 8.49 (1H, d, J = 5Hz), 8.22 (1H, d, J = 2Hz), 8.18 (1H, s), 7.38 (1H, s), 7.18 (1H , d, J = 8 Hz), 7.05 (2H, m), 6.46 (1H, d, J = 8 Hz), 2.65 (3H, s), 2.63 (3H, s).

Example 2 Compound 2 in Table 1

N- (3- (4- (2,4 dimethylthiazol-5-yl) pyrimidine-2-ylamino) phenyl) hydroxylamine (0.10 g, 0.32 mmol) obtained according to Example 1 and triethyl Acetyl chloride (25 ul) was added to a solution of amide (53 ul) in tetrahydrofuran (5 ml), and the mixture was stirred for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is purified by silica gel chromatography (eluted with ethyl acetate) and crystallized from ethyl acetate to give N- (3- (4- (2,4 dimethylthiazol-5-yl) pyrimidine-l- 2-ylamino) phenyl. Lu) N-hydroxyacetoamide (0.04 g, 35%) was obtained.

1H-NMR: 10.52 (1H, s), 9.71 (1H, s), 8.52 (1H, d, J = 5Hz), 8.01 (1H, s), 7.61 (1H, m), 7.26 (2H, m), 7.09 (1H, d, J = 5Hz), 2.65 (3H, s), 2.64 (3H, s), 2.20 (3H, s).

Example 3 Compound 3 in Table 1

N- (3- (4- (2,4 dimethylthiazol-5-yl) pyrimidine-2-ylamino) phenyl) hydroxylamine (0.10 g, 0.32 mmol) obtained according to Example 1 and triethyl Acetyl chloride (48 ul) was added to a solution of amide (98 ul) in tetrahydrofuran (5 ml), and the mixture was stirred for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is purified by silica gel chromatography (eluted with ethyl acetate) and crystallized from ether to give N-acetyl-N- (3- (4- (2,4-dimethylthiazol-5-yl) pyrimidine-2-ylamino) phen- L) Acetamide (0.05 g, 42%) was obtained. . ^ X :: (/ ((/

° (s Ήε) 83ζ ('(s Ήε) ε9' (zHe = f 'p

Ήΐ) 0ΓΖ '(ZH6 = f' P Ήΐ) εΓΖ '(ZH8' zH8 = f 'PP Ήΐ) 62''Ζ' (ω 'Η £) £ νί' (ω 'HI) 6S'Z' (ω 'H2 ) S9 "Z '(s Ήΐ) 2Γ8

'P' HT) 2S "8 '( ^s ' Ηΐ) ΖΖ · 6' ( ^s Ήΐ) ε9 ΐ: Η Ν-Ηΐ

° (ω Ή9) 06 '(ω Ή ^) 83

'(ω' HZ) SZ'Z '(s' m) WZ '(ZH8 = f' Ρ Ήΐ) Ζ0 "Ζ

'Ρ' Ηΐ) ΐ · Ζ '(ω' HT) 6S "Z

'Ρ' HI) SS'8 '( ^s Ήΐ) Ζ8 "6: Η Ν-Ηΐ

. Be ^ (((/

° (ZH8 = 1 "Ήε) 6.0

'(ω' H2) T9 "T '(s' HS) S9' (s

'Ρ' HT) 6S "Z '(s' Ηΐ) Μ) 8

'Ρ' HT) 2S "8 '( ^s ' Ηΐ) ΐΖ · 6 '( ^s ' Ηΐ) 0 · 0ΐ: Η Ν-Ηΐ

Ν- (/ -e (^ / one S—be; ^^ ίί (one S—one, ^ ^ one 'Ζ) →

° ( ^s Ήε) 90 '( ^s Ήε) ε22 nz' nz) wz

'(s' HS) S9 "2

'PP' HT) 8S "Z '(ZH8 = f' P 'Ηΐ) 9ΓΖ' (sjq Ήΐ) Ζ6" Ζ 'P' HI) SS'8 '( ^s ' HT) S8 "6: 顺 —HI

6ll600 / S00Zdf / X3d 93 OSSCll / SOOZ OAV 1H-NMR: 9.86 (1H, s), 8.50 (1H, d, J = 5Hz), 8.15 (1H, s), 8.02 (2H, d, J = 7Hz), 7.76 (1H, t, J = 8Hz) , 7.66 (1H, m), 7.60 (4H, m), 7.45 (1H, m), 7.38 (2H, m), 7.31 (1H, dd, J = 8Hz, 8Hz), 7.12 (1H, d, J = 5Hz), 7.01 (1H, d, J = 8Hz), 2.63 (3H, s), 2.61 (3H, s)

Example 8 Compound 8 in Table 1

N- (4- (2,4-dimethylthiazol-5-yl) pyrimidine-2-yl) benzene obtained by Production Example 4-1,3 diamine (0.30 g, l.Olmmol) and triethylamine (0.17 ml) Acetyl chloride (0.08 ml) was added to a solution of the above) in tetrahydrofuran (10 ml), and the mixture was allowed to stand at room temperature. Water was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration to give N- (3- (4 (2,4 dimethylthiazol-5yl) pyrimidine-2-ylamino) phenyl) acetamide (0.23 g, 67%). Obtained.

1H-NMR: 9.83 (s, 1H), 9.61 (s, 1H), 8.50 (d, 1H, J = 5Hz), 7.84 (s, 1H), 7.52 (m, 1H), 7.20 (m, 2H), 7.06 (d, 1H, J = 5Hz), 2.65 (s, 3H), 2.63 (s, 3H), 2.04 (3H, s).

Example 9 Compound 9 in Table 1

Using n-butyryl chloride, N- (3- (4 (2,4 dimethylthiazol-5yl) pyrimidine-2-ylamino) phenyl) butanamide was prepared in the same manner as in the production method of compound 8 in Table 1. Obtained.

1H-NMR: 9.77 (1H, s), 9.60 (1H, s), 8.50 (1H, d, J = 5 Hz), 7.90 (1H, s), 7.47 (1H, m), 7.21 (2H, m), 7.06 (1H, d, J = 5Hz), 2.64 (3H, s), 2.63 (3H, s), 2.28 (2H, t, J = 7Hz), 1.62 (2H, m), 0.93 (3H, t, J = 7Hz) _G

Example 10 Compound 10 in Table 1

Using iso-butyryl chloride, N- (3- (4 (2,4 dimethylthiazol-5-yl) pyrimidine-2-ylamino) phenyl) isobutanamide was prepared in the same manner as in the preparation of compound 8 in Table 1. Obtained.

1H-NMR: 9.72 (1H, s), 9.60 (1H, s), 8.50 (1H, d, J = 5 Hz), 7.95 (1H, s), 7.44 (1H, m), 7.20 (2H, m), 7.06 (1H, d, J = 5Hz), 2.64 (3H, s), 2.63 (3H, s), 2.62 (1H, m), 1.10 (6H, d, J = 6Hz). Qii¾ ^) i¾ gi M [soio]

'H · 0' (ω 'HT) 28 "T' ( ^s 'HS) S9' ( ^s 'HS) S9"2' ( ^z HS = f 'P' HT) 90 "Z '(ω' HZ) IZ -L

'(ω Ήΐ) 6Υί' (s Ήΐ) 68 "Ζ '(zHS = f' Ρ 'HT) 0S"8' ( ^s 'Ηΐ) 096' ( ^s Ήΐ) 80 ΐ: Η Ν-Ηΐ

^ ΐί¾ ^) ΐ¾ ΐί ^ ¾? No. [ζοτο]

'Ρ' HT) 0S "Z '(s Ήΐ) Ζ8" Ζ

'Ρ' HT) 0S "8 '( ^s ' HT) 6S" 6 '( ^s ' Ηΐ) ΐ8 · 6: Η Ν-Ηΐ

べェ: / 一 ε-(/ 一

( ^s Ήε) ε9 '( ^s Ήε) ε9' ( ^s ' Η · ε '( ^z He = f' p 'ΗΪ) 90''(ω' HZ) WL '(ω' HWL

'(ω' HT) 0S "Z '(s Ήΐ) 68" Ζ

'P' HT) 0S "8 '( ^s Ήΐ) 29"6' ( ^s Ήΐ) Ζ0 ΐ: Η Ν-Ηΐ

)

° (s' HS) 09 "2 '(s' HS) 9

'P Ήΐ) Ζ0 "Ζ' (ω 'H2) 62"Z' (ω 'H) SS'Z

'P' H2) 96 "Z '(s Ήΐ) 3Γ8' (zHS = f 'P' HT) 2S" 8 '( ^s Ήΐ) Ζ9 "6' ( ^s ΐ) ΐ2 ΐ: Η Ν-Ηΐ

X

[WHO]

6ll600 / S00Zdf / X3d LZ OSSCll / SOOZ OAV ° ( ^s Ήε) 09 "2 '(s' U £) WZ '(zHS = f' P Ήΐ) 80" Ζ '(ω' HT) S2 "Z '(ω' H2) 82" Z '(ω' HT) W

'P' Ηΐ) Μ) 8 '( ^s Ήΐ) ΐΓ8' ( ^z HS = f 'P' HI) SS'8 '( ^s ' Ηΐ) 696' ( ^s Ήΐ) 6ΐ ΐ: ΗΝ -Ηΐ

. ^ ^^ Bee ^ -Z- (/

° (zHZ = f '; Ήε) 98'(ω'H8) 62 "T '(ω'H2) 6S"T' (zH8 = f'H2) 0S "2 '(s' HS) S9' ( ^s Ήε 9 '(zHS = f' P Ήΐ) 90 "Ζ '(ω' H2) T2" Z '(ω

'Ρ' HT) 0S "8 '( ^s ' Ηΐ) 09 · 6 '( ^s ' HT) 9Z" 6: Η Ν-Ηΐ

. , Be ^

° ( ^z H8 = f 'Ήε) ΐ6' (ω Ή2) εεΐ ΐ (ω 'HS) 8S'I

'(zH8 = f''ΗΖ' Ζ '(s' HS) S9 "2 '(s' U £) wz '(zHS = f' P Ήΐ) 90" Ζ '(ω ΉΖ) ΙΖΊ' (ω

'Ρ' HT) 0S "8 '( ^s ' Ηΐ) 09 · 6 '( ^s ' Ηΐ) ΖΖ · 6: Η Ν-Ηΐ

(/-s— / —, ^ ^ one 'ζ)

° (ω Ήε) ε2ΐ ΐ '(ω ΉΖ) Ζν \' (ω Ήΐ) 39

'Η) 8ΓΙ' (ω Ήΐ) 3εζ ζ '(s Ήε) ε9' ( ^s 'nz) wz' ( ^z He = f 'p' HW '(ω' HS) OS "

'(ω' Ηΐ) ε · '(s' Ηΐ) 6

'P' HT) 0S "8 '( ^s ' HT) 6S" 6 '( ^s ' HT) 0Z "6: 顺 -HI

. ^ ^^ Be ^ (/ e

6ll600 / S00Zdf / X3d 83 OSSCll / SOOZ OAV

^ E / (Su¾s) 邈 ^^ / bebe (— S

[eno]

° ( ^s ' Hoof 9 '( ^s ' HZ) WZ

'P Ήΐ) 80 "Ζ' (ω 'H2) TS"Z' (ω 'H2) ZS "Z' (ω Ήΐ) 3Γ8 '(ω Ήΐ) 62" 8

'Ρ Ήΐ) 23 · 8' (ω 'Ηΐ) ΖΖ8' ( ^Ζ Η2 = Γ 'Ρ Ήΐ) 2Γ6' ( ^s ' Ηΐ) ΐΖ6 '( ^s ' Ηΐ) ΐ · 0ΐ: Η Ν-Ηΐ

° ( ^s ' H £) £ 9'Z '(s' HS) S9 "2

'PP

'Ηΐ) θε ·' (ω 'HZ) Z -L' (ω 'Ηΐ) 69 ·' (ω 'Ηΐ) 60 · 8' ( ^Ζ Η8 = Γ 'Ρ Ήΐ) 8Γ8' ( ^s 'ΗΙ) Ζ' 8

: Η Ν-Ηΐ

° -Μ (% L, ^§ οε · ο) (/ -e (^ / one s—be; ^^ ίί (one s—one, ^ ^ one 'ζ) →) -ε

)

. Transformation ε, 累 cumulative ^ I ( ^s os'o) rinse ^, ίίΰΗ /, ίί∑ =. ; (ιωοΐ) ve c ^ ^ i ^ o) (ρ¾ε

)

-Be (— S one, ^ ^ — 'Ζ) →)

° ( ^s Ήε) ε9 ′ ( ^s

'HS) 9' (s Ήζ) 88 · ε '(ω Ή2) 66 "9' (zHS = f 'Ρ Ήΐ) Ζ0" Ζ' (ω 'H2) S2 "' (ω 'HT) 6S" Z

'(ui Ήΐ) ΐ3 ·' (s Ήΐ) 06 "Ζ

'Ρ' HT) 0S "8 '( ^s ' Ηΐ) 9 · 6' ( ^s Ήΐ) Π ΐ: Η Ν-Ηΐ

. (-E ^--Z- (/ -e

6ll600 / S00Zdf / X3d 63 OSSCll / SOOZ OAV G) Phospho-dimethylhexafluorophosphite) (0.18 g) was left at room temperature at room temperature. Water was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluted with ethyl acetate: n-hexane = 2: 1), and ethyl acetate and n-hexane were added. (4 (2,4 dimethylthiazol-5-yl) pyrimidine-2-ylamino) phenyl)-(5-methylthiophene) 2-carboxamide (0.09 g, 65%) was obtained.

1H-NMR: 10.06 (1H, s), 9.67 (1H, s), 8.52 (1H, d, J = 5 Hz), 8.08 (1H, s), 7.84 (1H, m), 7.53 (1H, m), 7.26 (2H, m), 7.08 (1H, d, J = 5Hz), 6.92 (1H, m), 2.64 (3H, s), 2.61 (3H, s) ₀

Example 23 Compound 25 in Table 1

Using 2,4 dimethylthiazole-5-carboxylic acid, N- (3- (4- (2,4 dimethylthiazol-5-yl) pyrimidine-2 —Iramino) phenyl) -1- (2,4 dimethylthiazole) -5-carboxamide

1H-NMR: 10.02 (1H, s), 9.68 (1H, s), 8.51 (1H, d, J = 5Hz), 8.06 (1H, s), 7.52 (1H, m), 7.23 (2H, m), 7.08 (1H, d, J = 5Hz), 2.66 (3H, s), 2.63 (3H, s), 2.62 (3H, s), 2.55 (3H, s)

Example 24 Compound 27 in Table 1

2-chloro-N- (3- (4 (2,4 dimethylthiazol-5-yl) pyrimidine-2-ylamino) phenyl) acetamide was obtained by the same procedure as in the preparation of compound 8 in Table 1 using chloroacetyl chloride. Got.

1H-NMR: 10.2K1H, s), 9.69 (1H, s), 8.51 (1H, d, J = 5Hz), 7.92 (1H, s), 7.54 (1H, m), 7.24 (2H, m), 7.08 (1H, d, J = 5Hz), 4.25 (2H, s), 2.65 (3H, s), 2.64 (3H, s).

Example 25 Compound 28 in Table 1

N- (4- (2,4-dimethylthiazol-5-yl) pyrimidine-2-yl) benzene obtained by Production Example 4-1,3 diamine (0.30 g, l.Olmmol) and triethylamine (0.17 ml) ) Was added to a solution of (10) in tetrahydrofuran (86 ml) and left at room temperature for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, and dried over magnesium sulfate. After drying, the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated crystals were collected by filtration to give N- (3- (4 (2,4 dimethylthiazol-5-yl) pyrimidine-12-ylamino) phenyl) methanesulfonamide (0.29 g, 76%).

1H-NMR: 9.68 (1H, s), 9.65 (1H, s), 8.51 (1H, d, J = 5Hz), 7.61 (1H, m), 7.57 (1H, m), 7.25 (1H, dd, J = 8Hz, 8Hz), 7.08 (1H, d, J = 5Hz), 6.83 (1H, m), 3.00 (3H, s), 2.65 (3H, s), 2.64 (3H, s).

Example 26 Compound 29 in Table 1

N- (3- (4 (2,4 dimethylthiazol-5-yl) pyrimidine-2-ylamino) phenyl) butanesnolide was prepared using n-butanesulfuric acid and obtained in the same manner as in the preparation of compound 28 in Table 1. Honamide was obtained.

1H-NMR: 9.67 (2H, s), 8.50 (1H, d, J = 5Hz), 7.57 (2H, m), 7.23 (1H, dd, J = 8Hz, 8Hz), 7.08 (1H, d, J = 5Hz), 6.82 (1H, d, J = 7Hz), 3.09 (2H, t, J = 8Hz), 1.67 (2H, m), 1.35 (2H, m), 0.83 (3H, t, J = 8Hz).

Example 27 Compound 30 in Table 1

N- (3- (4 (2,4 dimethylthiazol-5-yl) pyrimidine-2-ylamino) phenyl) benzenesulfonamide was prepared by using benzenesulfuryl chloride and the same procedure as in the preparation of compound 28 in Table 1. Got.

1H-NMR: 10.18 (1H, s), 9.62 (1H, s), 8.49 (1H, d, J = 5 Hz), 7.80 (2H, d, J = 7 Hz), 7.53 (5H, m), 7.12 (1H , dd, J = 8Hz, 8Hz), 7.06 (1H, d, J = 5Hz), 6.68 (1H, d, J = 8Hz), 2.65 (3H, s), 2.62 (3H, s).

Example 28 Compound 31 in Table 1

N- (3- (4 (2,4 dimethylthiazol-5-yl) pyrimidine-2-ylamino) phenyl) obtained according to Example 26) 2 chloroacetamide (0.10 g, 0.27 mmol) and morpholine ( Potassium carbonate (70 mg) and a catalytic amount of potassium iodide were added to a 47 ul) N, N dimethylformamide solution (5 ml), and the mixture was stirred at 80 ° C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluting with chloroform: methanol = 19: 1) to give N- (3- (4- (2,4 dimethylthiazol-5-yl) pyrimidine-2-ylamino) phenyl. Le) -2 ( ^s Ήε) ε9

'(s Ήε) 9' (s Ήε) 6ε · '( ^s ' HS) OO'

'P' HT) TS "Z '(s Ήΐ) Ζ6" Ζ

'P' HT) 0S "8 '( ^s ' HT) 6S"6' ( ^s Ήΐ) 29 "6: 顺 -HI

(/ -E (, ^ / one S—be; ^^ fi (one S—one, ^ ^ one 'Ζ) →)

( ^s ' Η6) 0 · ΐ '( ^s ' H9) S9' ( ^s ΉΖ) 9ΐτ '(ω' HHε '( ^z HS = f' Ρ 'Ηΐ) ΗΐΖΟ' (ω 'HZ) WL

'Ρ Ήΐ) 6η' (s Ήΐ) 26 "Ζ 'Ρ' HT) 0S" 8 '( ^s ' H2) 09 "6: Η Ν-Ηΐ

° ( ^s 'm) f9'z' ( ^s Ήε) 99

'(ω' Η2) 0Γε

'Ρ Ήΐ) 60 "Ζ' (ω 'H2) 92"Z' (ω 'HT) 8S "Z' (s Ήΐ) ΐ6" Ζ 'Ρ' HT) TS "8 '(sjq' HS) 6'8 '( ^s ' Ηΐ) · 6 '( ^s ' Ηΐ) 8 · 0ΐ: Η Ν-Ηΐ

^^ Μ / Μ ^ ^ Μ. , (, ^ ^ E, ^ ci, —S) —

) -ε)

One

° (ω 'Η S' (s' HZ) WZ

'(s' HS) 9 '(s Ή2) εΓε' (ω ') WZ' (zHS = f 'P Ήΐ) Ζ0 "Ζ' (ω ^l WZ) Z'L '(zH8 = f' P

'P' HT) 0S "8 '( ^s ' Ηΐ) 09 · 6 '( ^s ' Ηΐ) ΐ9.6 · 顺 -HI

. (% 96 Ηνϋ)

6ll600 / S00Zdf / X3d OSSCll / SOOZ OAV

^{° (s Ή6) 8ε · ΐ} '(s Ήε) ε9'(s' HS) S9

'(ZHST

'Ρ' HT) OS "Z '(s Ήΐ) 88" Ζ

'P' HT) 0S "8 '( ^s Ήΐ) 29"6' ( ^s ' HT) S8 "6: Η Ν-Ηΐ

(/ S / —, ^

° ( ^s Ή6) ο 'ΐ' ( ^s Ήε) ε9 '( ^s

'HS) S9 "2

'P Ήΐ) 90 "Ζ' (ω 'H2) S2"

'(ω' HT) 2S "Z '(s Ήΐ) Ζ8" Ζ

'( ^s ' Ηΐ) 08 · 6: Η Ν-Ηΐ

°, (/

—, ^ / — 'Ζ) →) — ε) -Ν-

° (ω 'HZ) ZVZ

'(s' HS) S9 "2 '(s' HS) S9" 2 '(zH9 = f''H2) 09 "S' (zHS = f 'P Ήΐ) 90"Ζ' (ω 'HZ) ZZ' L '(ω

'Ρ' HT) 0S "8 '( ^s Ήΐ) 29"6' ( ^s ' Ηΐ) 68 · 6: Η Ν-Ηΐ

° -Μ Λ ^^ (-e (, ^ / yz

° ( ^s 'm) z9'z' ( ^s 'm) f9'z' ( ^s

'HZ) LVf' (ω 'Ηΐ) ΐ8.9

'PP' HT) S2 "Z '(ω' H2) TS" Z '(ω' HS) SS "Z '(ω Ή2) ΐ9" Ζ

'P' Ηΐ) · 8 '( ^s ' Ηΐ) 0Γ6 '( ^s ' HT) 6Z "6: 顺 -HI

. ¾¾, ^ bebe-e (/ e

Bae

6ll600 / S00Zdf / X3d εε OSSCll / SOOZ OAV Using N-t butoxycarbol-γ gamma-aminobutanoic acid, the same procedure as in the method for producing compound 23 in Table 1 was used to prepare 4- (t-butoxycarbo-lamino) N— (3- (4 (2,4-dimethylthiazole-5 Yl) pyrimidine 2 ilamino) phenyl-butanamide. 1H-NMR: 9.80 (1H, s), 9.61 (1H, s), 8.50 (1H, d, J = 5 Hz), 7.89 (1H, s), 7.48 (1H, d, J = 7 Hz), 7.21 (2H , m), 7.06 (1H, d, J = 5Hz), 6.83 (1H, m), 2.97 (2H, dd, J = 6, 13Hz), 2.64 (3H, s), 2.63 (3H, s), 2.30 (2H, t, J = 7Hz), 1.70 (2H, m), 1.38 (9H, s).

Example 37 Compound 41 of Table 1

2- (t-Butoxycarbolamino) N- (3- (4 (2,4-dimethylthiazole-5-yl) pyrimidine-2-ylamino) phenyl) acetamide (0.31 g, 0.68 mmol) obtained in Example 34 ) In 1,4 dioxane (10 ml) was added 4N hydrochloric acid Zl, 4 dioxane (5 ml), and the mixture was allowed to stand at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The resulting precipitate was collected by filtration to give 2 amino-N- (3- (4- (2,4dimethylthiazol-5-yl) pyrimidine-2-ylamino). Ferure) acetoamide 'hydrochloride (0.25 g, 94%) was obtained.

1H-NMR: 10.50 (1H, s), 9.78 (1H, s), 8.52 (1H, d, J = 5Hz), 8.21 (3H, brs), 7.90 (1H, s), 7.58 (1H, m), 7.28 (2H, m), 7.10 (1H, d, J = 5 Hz), 3.78 (2H, m), 2.67 (3H, s), 2.65 (3H, s).

Example 38 Compound 42 in Table 1

Using 3-((t-butoxycarbolamino) N- (3- (4 (2,4 dimethylthiazol-5yl) pyrimidine-2-ylamino) phenyl) propanamide obtained in Example 35, Table 1 3 amino-N- (3- (4- (2,4 dimethylthiazol-5yl) pyrimidine-2-ylamino) phenyl) propanamide was obtained in the same manner as in the production method of compound 41.

1H-NMR: 10.1K1H, s), 9.68 (1H, s), 8.51 (1H, d, J = 5 Hz), 7.88 (4H, m), 7.52 (1H, d, J = 8 Hz), 7.26 (2H, m), 7.08 (1H, d, J = 5 Hz), 3.08 (2H, m), 2.73 (2H, t, J = 7 Hz), 2.66 (3H, s), 2.64 (3H, s).

Example 39 Compound 43 in Table 1

4- (t-butoxycarbolamino) N- (3- (4 (2,4 . ^ / ^ /, ^ A _{ N- (

° ( ^s Ήζ) Ζ9'Ζ '( ^s ' nz) wz

'(s'Ηΐ)' P 'HT) TS "8'(s' HI) SS'8 '( ^s ' Ηΐ) 9.8' ( ^s Ήΐ) 29" 6: 顺 -HI

(% 0)

/ 一一_{ N-

-9--

, 鷇鷇 s 教 ^ ^ ^ ^ mm-^ n ^ n (OW

Be (— S— one, ^ ^ — 'Ζ) →) -N ^ ¾ C) T ^) H} ¾

8 ^^ o) i¾ iHM [εειο]

° ( ^s 'HS) 9' (s 'HS) S9 "2' (zH6 = f 'HZW' ( ^Z H8

'PP' ΗΙ) ίΖΊ

'(ω' HI) 8S'Z '(ω Ήΐ) Ζ9 "Ζ

'P' HT) TS "8 '( ^s ' Ηΐ) 69 · 6 '( ^s ' Ηΐ) Ζε · 0ΐ: Η Ν-Ηΐ

. Be (be / H / fH— S 'Ζ' Ζ)-

-Be (— s— one,

¾ii¾ «8S 呦 ^^ O)" [挲, 、, ¾f ficiH /-^^ ci / fH— S 'Z' Z

° (ω 'H2) Z8 "T

'; ΉΖ) ΥΖ

'(s' HS) 9' (s Ήε) 99 '(ω' H2) S8 "2 '(zHS = f' P Ήΐ) Ζ0" Ζ '(ω' HZ) £ Z'L '(zH8 = f' Ρ 'HT) TS "Z' (ω 'Η) 68

'Ρ' HI) IS'8 '( ^s ' HT) S9 "6 '( ^s ' Ηΐ) 96 · 6: Η 顺-Ηΐ

° -Μ

6ll600 / S00Zdf / X3d 9ε OSSCll / SOOZ OAV 1H-NMR: 9.56 (1H, s), 8.67 (1H, s), 8.50 (1H, d, J = 5Hz), 7.62 (1H, s), 7.41 (1H, m), 7.15 (2H, m), 7.05 (1H, d, J = 5Hz), 6.46 (1H, t, J = 6Hz), 4.12 (2H, q, J = 7Hz), 3.87 (2H, d.J = 6Hz), 2.65 (3H, s) , 2.63 (3H, s), 1.21 (t, J = 7Hz) _G

Example 43 Compound 50 of Table 1

N- (3- (4 (2,4 dimethylthiazol-5-yl) pyrimidine-2-ylamino) phenyl obtained according to Example 42) N, -ethoxycarbonmethylperyl (0.20 g, 0.47 mmol) To a solution of (4) in tetrahydrofuran (6 ml) and methanol (4 ml) was added a 4M aqueous solution of lithium hydroxide (0.59 ml), and the mixture was stirred at 60 ° C for 30 minutes. After cooling the reaction solution to room temperature, water and a 1N aqueous hydrochloric acid solution were added to make the solution acidic, and the solution was left at room temperature. The resulting precipitate was collected by filtration to give (3- (3- (4 (2,4 dimethylthiazol-5-yl) pyrimidine-2-ylamino) phenyl) ureido) acetic acid (0.17 g, 91%) Got.

1H-NMR: 12.52 (1H, brs), 9.55 (1H, s), 8.64 (1H, s), 8.50 (1H, d, J = 5Hz), 7.61 (1H, s), 7.39 (1H, m), 7.16 (2H, m), 7.05 (1H, d, J = 5Hz), 6.37 (1H, t, J = 6Hz), 3.80 (2H, d, J = 6H,), 2.65 (3H, s), 2.64 ( 3H, s).

Example 44 Compound 51 of Table 1

Using 3,3,3 trifluoropropionic acid, N- (3- (4- (2,4 dimethylthiazol-5-yl) pyrimidine-2 There was obtained (ilamino) phenyl) (3,3,3-trifluoropropane) amide.

1H-NMR: 10.20 (1H, s), 9.69 (1H, s), 8.52 (1H, d, J = 5 Hz), 7.92 (1H, s), 7.54 (1H, d, J = 8 Hz), 7.25 (2H , m), 7.08 (1H, d, J = 5Hz), 3.51 (2H, q, J = 9Hz), 2.64 (3H, s), 2.64 (3H, s).

Example 45 Compound 52 of Table 1

N- (4- (2,4-dimethylthiazole-5-yl) pyrimidine-2-yl) benzene obtained by Production Example 4-1,3 diamine (0.10 g, 0.34 mmol), 4 (dimethylamino) butamate Acid hydrochloride (62 mg) and diisopropylethylamine (140 ul) in N, N dimethylformamide (5 ml) were added to a BOP reagent (benzotriazole-1-yloxytris (dimethylamino) phospho-dimethylhexafluoate). Lophosphite) (0.18 g) was allowed to stand at room temperature. Water was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was removed under reduced pressure. 'ΗΖ ^ Ζ'Ζ' (zH9 = f '' HZ) £ L '£' (zH8 = f 'P' HT) S8 "9 '(zHS = f' P Ήΐ) 60" Ζ '(ΖΗ8' zH8 = f 'PP' HT) S2 "Z '(ω' H2) 6S" Z

'P' HT) TS "8 '( ^s ' Ηΐ) 69 · 6 '( ^s ' Ηΐ) ΐ8 · 6: Η Ν-Ηΐ

99ί¾? ^) Ι¾ 8Η ¾Ϊ [Ο ^ ΐΟ] ° ( ^s ' HS) S9 "2 '(s Ήε) 9' (zH8 = f '' HS) 99 '(zH8 = f''HS)6' (zHS = f 'P

Ζ) 90 ”Ζ '(ω' H2) T2" Z '(ω' Ηΐ) ΐε · '(ω' HT) 0S "Z '(ΖΗ8—1"' Ρ Ήΐ) Ζ9 "Ζ '(s Ήΐ) 98 "Ζ

'Ρ' HT) 0S "8 '( ^s Ήΐ) 29"6' ( ^s ' Ηΐ) 8 · 6: Η 顺-Ηΐ

Base ^ ΰ: (/ one ε-base; ^ ίί) ε (/ ェ

° ( ^s ' HZ) WZ '( ^s Ήε) 99' ( ^z H ^ = f 'P' HS) 06 '( ^z H8 = f' P

Ήΐ) 26 "9

'PP' HT) S2 "Z 'P' HI) SS'Z '(sjq

Ήΐ) 09 "Ζ '(s' HT) S8" Z

'P' HT) SS "8 '(sjq' Ηΐ) 8 · 6 '( ^s ' HT) 2Z" 6: 顺 -HI

. ^ ^ _{ N- (

ヽ ¾r¾ Rinse / ^ ^

° (ω 'Η 6

'HZ) WZ' (s Ήε) 9 '( ^s ' HS) 99 "2 '( ^s ' HS) SZ" 2

'(s' HS) 9Z "2 '(ω' H 0

'(ZH6 = f' P 'HT) TS "Z' (s Ήΐ) 88" Ζ 'P' HI) IS'8 '( ^s ' Ηΐ) 696' ( ^s Ήΐ) 20 ΐ '(sjq' HI ) SS'0I: 顺 -HI

. (% 6S §90)

(-E (, ^

^

Stop

^ i ^ m ^^ ^ ^^ ^^ ^ m °

6ll600 / S00Zdf / X3d ζε OSSCll / SOOZ OAV ° ( ^s ' m) zo'z '( ^s ' m) wz' ( ^s Ήζ) ζνζ '(^' HZ) \ ZL '(ω

Ήΐ) εεζ '(ω' Hi) es "Ήΐ) 28"'(ω' HI) SS'8 '( ^s Ήΐ) εζ6' ( ^s Ήΐ) ε8 · 6: Η 顺 -HI

° -Μ Λ ^ ^ (-e (,

^ m ^ u ^ ^ ヽ ¾r¾ve, ^ (/ — / —, ^ ^ ー s)

'(s' HS) 9

'PP Ήΐ) 8ΓΖ

'P Ήΐ) 9Υί' (s Ήΐ) ΐ8 "Ζ

'( ^s ' HT) 0S "6 '( ^s ' HT) 6S" 6: Η Ν-Ηΐ

. ^^,

09 呦 ^^ "[挲 1 \ Μ [ε ^ το]

° ( ^s ' H9) S9 '(s' H2) Sre

'PP Ήΐ) 6ΓΖ

'(ω Ή9) 2 ^ "' (s 'HT) 28"Z' (zHS = f 'P' Ηΐ) 6 · 8 '( ^s ' Ηΐ) 09 · 6 '( ^s ' Ηΐ) 89 · 6: 顺-HI

) One ε)

^{° (s 'm) Z9'z'} (S 'HS) S9 "2' {= [

'Ήΐ) εΓΖ

'(ui

: Η Ν-Ηΐ

. Bebebe: ^ ^ — ― (/ ェ

-Be (— s— one,

6ll600 / S00Zdf / X3d 8ε OSSCll / SOOZ OAV

: Η Ν-Ηΐ

°: · ¾¾, ^ Bebe (/ -e (, ^

Be (s one, ^ ^, one 'ζ) →)

° ( ^s ' Hoof 0 '(s' HZ Z

'P' HS) S8 "2 '(zH9 = f' P 'HT) S8"9' (ω 'Η2) 9ΓΖ' (zH8 = f Ή \) ίΥί '(s' HT) 8Z "Z

'P Ήΐ) 62 "8' ( ^s ' Ηΐ) Ζε · 6 '( ^s ' Ηΐ) ΐ8 · 6: Η Ν-Ηΐ

. , 4 ¾ ~ (/ ェ

(/ One s-

° (s Ήε) ΐ0 "2 '(s Ή £) ΖΥ' P 'Ηΐ) ε89' (ω 'Η2) 9ΓΖ' (s' UZ) LVL

'P' HT) W '(s' HT) 2Z "Z

^{Ήΐ) 62 "8 '(s} ' Ηΐ) Ζε · 6' (s Ήΐ) 28" 6: Η Ν-Ηΐ

. ^ (/ {{^^ -z- ^ (^ (1 s 1, ^ Mar N 'N (/ — / —, ^ ^ one,-(/ fi, ^ ^

ー ε) S) ― 、

,! Uisq

pu i s ^ jo punof) ¾STO Suopm ^: ve; ^-/, ε

呦 ^ [挲 ^ M [9W0] ° ( ^s Ή £) Ζ0'Ζ '(s' HS) S9 "2'(s' HS) S9" 2 '(zHS = f' P 'Ηΐ) Μ) Ζ '(zH6 = f' P ΉΖ) 6Υί

! "'P' H2) 99" Z '(zHS = f' P 'Ηΐ) 8 · 8' ( ^s ' Ηΐ) · 6 '( ^s ' Ηΐ) 08 · 6: 顺 -HI

. , (((, ^

'τ all: ^ (s—

Be (— S one, ^ ^ — 'Ζ) →)-

6ll600 / S00Zdf / X3d 6ε OSSCll / SOOZ OAV '(s' HZ) WZ '(ω' HS) 60 "Z '(ω' HS) 62" Z

'Ρ' HT) OS "Z 'Ρ' HT) ZS" Z

'(s Ήΐ) ΐ6 "Ζ

'P' HT) TS "8 '(s' HT) Z9" 6 '( ^S ' HT) 0Z "6 '( ^s ' Ηΐ 66: Η Ν-Ηΐ

. ^ _{{ Ν-

) ΖΟ "Ζ '(ΖΗ9

'P' HT) S8 "Z

'P' HI) IS'8 '( ^s ' Ηΐ) 9 · 6 '( ^s ' Ηΐ) ΐ · Οΐ: 顺-HI

. ^ ^^ Bee ^ -Z- (/

° ( ^s Ήε) ε9

'(s' HS) 99 "2' (s' Ηζ) 6ε · 'Ρ Ήΐ) ΖΟ" Ζ' Ρ 'Η2) 3ΓΖ' (ω 'HS) SS "Z

'Ρ ^L WZ) ZL'L' Ηΐ) ΐ3.8 '( ^s ' HT) 6S "6 '( ^s ' HT) S9" 6: Η Ν-Ηΐ

. ¾¾, ^ bebe-(/-(

20ΐί¾? ^) Ϊ́¾ 89ί ^ ¾ϊNo. [Oeio]

° ( ^s

'HS) S9 "2'(s' HS) 99

'P' Η Ζΐ

'(ZH8 = f' P 'H2) SZ "Z

'P' HI) IS'8 '( ^s ' Ηΐ) 89 · 6' ( ^s Ήΐ) 3ΐ ΐ: 顺 -HI. Be (be / fH S 'Z' S) — (/ -e (^ / one S

呦 ^^ O) "[挲, 、, ¾f ficlH /-cl ^ cl / fH S 'Z' Z

° ( ^s Ήε) ε9 "2 '(s Ήε) 99' ( ^s Ήε) ε6 '(zHe = f' ρ Ήΐ) ζο” ζ '(zH6 = f' p 'HZ) 9VL

6ll600 / S00Zdf / X3d 017 OSSCll / SOOZ OAV 2.62 (3H, s).

Example 61 Compound 26 in Table 1

3 N- (3- (4- (2,4 dimethylthiazol-5-yl) pyrimidine-2) is obtained by the same procedure as in the preparation of compound 23 in Table 1 using chlorothiophene-2-carboxylic acid. (Illamino) phenyl) -2 (3-chlorothiophene) carboxamide was obtained.

1H-NMR: 10.10 (1H, s), 9.70 (1H, s), 8.52 (1H, d, J = 5Hz), 8.10 (1H, s), 7.91 (1H, d, J = 5Hz), 7.52 (1H , m), 7.28 (2H, m), 7.21 (1H, d, J = 5 Hz), 7.09 (1H, d, J = 5 Hz), 2.64 (3H, s), 2.62 (3H, s).

Example 62 Compound 44 in Table 1

2-amino-N- (3- (4- (2,4 dimethylthiazol-5-yl) pyrimidine-2-ylamino) phenyl) acetamide 'hydrochloride (0.10 g, 0.26 mmol) obtained according to Example 37 To a solution of triethylamine (0.06 ml) and tetrahydrofuran (5 ml) was added acetyl chloride (0.02 ml), and the mixture was allowed to stand at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration to give 2-acetylamino-N- (3- (4 (2,4dimethylthiazol-5yl) pyrimidine-2-ylamino) phenyl) acetamide (0.06 g, 58%).

1H-NMR: 9.86 (1H, s), 9.64 (1H, s), 8.50 (1H, d, J = 5Hz), 8.16 (1H, m), 7.88 (1H, s), 7.52 (1H, m), 7.23 (2H, m), 7.07 (1H, d, J = 5 Hz), 3.87 (2H, d, J = 6 Hz), 2.65 (3H, s), 2.63 (3H, s), 1.89 (3H, s).

Example 63 Compound 45 in Table 1

Using the 3 amino-N- (3- (4- (2,4 dimethylthiazol-5-yl) pyrimidine 2-ylamino) phenyl) propanamide obtained in Example 38, the process for producing compound 44 in Table 1 was carried out. By the same operation, 3-acetylamino-N- (3- (4- (2,4-dimethylthiazol-5-yl) pyrimidine-2--2-ylamino) phenyl) propanamide was obtained. 1H-NMR: 9.86 (1H, s), 9.64 (1H, s), 8.50 (1H, d, J = 5Hz), 8.16 (1H, m), 7.88 (1H, s), 7.52 (1H, m), 7.23 (2H, m), 7.07 (1H, d, J = 5 Hz), 3.87 (2H, d, J = 6 Hz), 2.65 (3H, s), 2.63 (3H, s), 1.89 (3H, s).

Example 64 Compound 46 in Table 1 80Ιί¾? ^) Ϊ́¾ 19 \ Μ [63 TO]

° ( ^s ' HZ) WZ '( ^s ' HS) Z9 "2

'(ω' Η2) 0Γε '(ω' H2) 96 "S

'Ρ ^l WZ) ZVL' Ρ 'HT) TS "8' (sjq 'H2) S6"8' ( ^s 'Ηΐ) 69 · 6' ( ^s Ήΐ) 93 ΐ: 顺-Ηΐ

. :

^ A ^ ^. (^ ^^^ ^ -ζ) -z- (/ -e (, ^ / one S—be fi (/ s— / —, ^ / ー 'ζ) →)

(/ -E

One / —, ^ ^

02Ιί¾? ^) Ι¾ 99ί ^ ¾ϊNo. [83 TO]

° ( ^s Ήε) ε9

'(s' HS) S9 "2' (s Ή2) ΐΓε '(ω' H) S9'S

'P' H2) SS "Z

'( ^s ' HT) 8S "6 '( ^s ' Ηΐ) 09 · 6: Η Ν-Ηΐ # θ) ¾-.

（(, ^ / — Be; ^^ (one s—one, ^ ^ one 'ζ) →) →)

. (-E

'(s' HS) S9 "2 '(s' HS) S9" 2

'P Ήΐ) 90 "Ζ' (ω 'HZ) £ Z'L

'(s Ήΐ) Ζ8 "Ζ' (ω Ήΐ) 26" Ζ '(zHS = f' P 'HT) 0S "8' ( ^s Ήΐ) 29" 6 '( ^s ' Ηΐ) 98 · 6: Η Ν- Ηΐ

— / —,

One / —, ^ ^ ー 'ζ) →) -ε)

6ll600 / S00Zdf / X3d zv OSSCll / SOOZ OAV

° (ω 'ΗΖ) Ζ ^ \' ( ^S 'HWZ' ( ^Ζ Η9 = Γ '' ΗΖ 'Ζ ( ^S ' HZ) WZ '( ^s ' HS) S9 "2' ( ^z H9 = f '' Η 9ΐ · Ε '(s

'Ρ

'Ρ' Ηΐ) ΐ3 · 8 '( ^s ' HT) SZ "6 '( ^s ' Ηΐ) 8Γ6: Η Ν-Ηΐ

°-Λ (% οζ, ΐ · ο), ^ べ ίί, ίί ε-(/ -e {^ j. ^ Yz- ^ (^ (one s one, m ^ m. ϊίkyo ^^^^^ m ^ m ^^ §S2)

One / —, ^

'(ω' Ηΐ) 09 · ΐ '(ω' H2) 0Z "T-S8" T '( ^s ' Hoof 0 '(ω' HS) SS — S9 '( ^s ' HS) S9 "2 '( ^s ' HS) 99 '(ω' HT) eO "S '(ω' Ηΐ) 88 · ε '(ω' ΗΪ) Ϊ !!"'Ρ' HT) 90 "Z '(ω Ήζ) ζζ-∑' (ΖΗ8 'HDLVL' (ΖΗ = ί "'Ρ' HT) 0S" 8 '( ^s Ήΐ) 29 "6' ( ^s ' HT) S8" 6: Η Ν-Ηΐ. ^^ be ^ one by one ^^ one ^ (/ -E (/ /

° (s'HS) S9 "2 '(s'HS) 99

'PP' HT) ZS "Z

'P' Η ΟΓΖ '(ZH8 = f' P 'H2) 9Z "Z' (ΖΗ8

'P' HI) IS'8 '(ZHS

'P Ήΐ) ΐΓ6' ( ^s ' Ηΐ) 99 · 6 '( ^s ' HWOT: Η Ν-Ηΐ

6ll600 / S00Zdf / X3d εΐ7 OSSCll / SOOZ OAV Sajik, r = 1 ^ 9 :, ^^ 餱 Κ866Κ S90S- SSOSd ΐΓ ° Ν ΖΠ. Λ

IBomof 09 3

[99 TO]

°: ε-— VOl つ OV 丄 O 丄丄丄 o 丄 :) VOV OVO :) 丄 :) OOO 000— <s) s Violent f ^ S¾Q¾Ls— o 丄 :) VW VOV

W 丄 DIV ODD VOO IVI VDD 丄丄 V VOO- (S) I each f ^ ffl ^ i ^ S insert 一 έ

VNd. ^ Sect

Tsutsuo V) EfspH

¾Suzu ^ — ^ ζέΰ— (υ

° (s 'HS) S0 "2' (s 'HS) Z0"2' (s 'HS) SS "2' (s Ήε) ΐ9

'P Ήΐ) 8ΓΖ

'P' HT) 8S "8 '( ^s ' Ηΐ) 06 · 8' ( ^s ' Hl) Z £ '6: Η Ν-Ηΐ

. ^ (/ ^ ^ S (/ /

M ^ ¾¾o) o ^ λ) τ 挲, ¾f ¾ve / / ε ^ ζ

89 呦 ^^ θ) ΐ 挲 Zl M i 910]

^{° (s' m) wz '} (s' m) fvz' (S 'HS) WS

'(s' HS) T9 "2

'PP' HT) TS "Z

'P' HT) 6S "8 '( ^s ' Ηΐ) 98 · 8 '( ^s ' Ηΐ) 08 · 6: Η Ν-Ηΐ

. ^ (/ ^ ^ 1,-(/ /

M ^ ¾¾O) 0 ^ λ) τ 挲, ¾f ¾ve / ェ cH-— Q ζ

69 呦 ^^ θ) ΐ 挲 \ L½W Κ9Ϊ0]

° (s 'HS) S0 "2' ( ^s ^l m) zvz '(s Ήε) ε9"2' ( ^s 'm) wz' (zHe = f 'p' HT) SO "Z '(zH8 = f' p Ήΐ) πζ ζ '(zH8 = f

'P' HT) SS "Z '(s' HT) 9Z" Z

'( ^s Ήΐ) 82 "6' ( ^s ' HT) ZS" 6: Η Ν-Ηΐ

. ^ （-E ^ ー 2 — (/ ^ ^ ー S

6ll600 / S00Zdf / X3d key OSSCll / SOOZ OAV It was identical to the sequence of the offspring.

[0167] The amplified Aurora 2 kinase encoding gene was transformed into an E. coli expression vector.

It was introduced into pET32a (Novagen) to prepare a recombinant. Recombinants are described in Ambrook et al., "Molecular Cloning-Experimental Manual, Second Edition (1989 Cold Spring Harbor Laboratory press)" and Ausubel et al., "Current Protocols in Molecular Biology, (1999 John Wiley and Sons Inc. .) ".

[0168] Thereafter, the recombinant was introduced into Escherichia coli BL21R (Novagen) for large-scale expression of protein to prepare an Escherichia coli strain for large-scale expression of Aurora 2 kinase.

[0169] An Escherichia coli strain for large-scale expression of Aurora 2 kinase was cultured in an LB medium containing Ampidlin (50 ug / ml). After culturing with shaking at 37 ° C for 1 hour, the culture temperature is set to 25 ° C and the final concentration is O.lmM IPTG (SIGMA) to induce the expression of Aurora 2 kinase. C. The cells were cultured with shaking for 24 hours. Thereafter, the culture solution was centrifuged at 7000 rpm for 10 minutes to recover the cells.

[0170] The recovered cells were treated with 36 ml of lysis buffer [50 mM Tris pH 6.8, 150 mM NaCl, 20 mM β-Glycerophspate, 0.3 mM Na3V04, 50 mM NaF, 2 mM PMSF (fluoromethyl methyl sulfol), protease inhibitor Cocktail tablet (Boehringer Mannheim) 1 tablet] and sonicated. Further, 4 ml of 10% NP-40 (Wako Pure Chemical Industries) was added to dissociate non-specific binding between proteins.

[0171] Thereafter, the recombinant Aurora 2 kinase in the solution was adsorbed to N-NTA agarose beads (QIAGEN), and the beads to which the recombinant Aurora 2 kinase was adsorbed were added to 50 ml of K buffer (1M

It was washed with KCl / lxTNT) and G buffer (30% Glycerol, 0.5M KC1 / lxTNT) to obtain Aurora 2-kinase.

[0172] (2) Aurora 2 Kinase Atsushi

To each well, 1.5 μl of buffer for enzyme reaction (200 mM Tris-HCl (pH 7.0), 100 mM MgC12), 1.5 μl of 50 mM dithiothreitol, 1.5 μl of ImM peptide substrate [LRRASLG], and the compound 1.5 μl of the added DMSO solution was added.

[0173] 1.5 µl of Aurora 2 kinase (lmg / ml) diluted in an enzyme diluent [50 mM Tris-HCl (pH 6.8), 200 mM NaCl, 50% Blank) Added to all wells. 1.5 1 of enzyme diluent containing no Aurora 2 kinase was added to a “blank” well. The “total” well contained 1.51 calories of a DMSO solution of the compound without added compound.

[0174] Next, 5ul of a 30 M ATP solution containing 1.2 µCi [(32P) ATP (Muromachi Yakuhin, specific activity> 3500 Ci / mmol)] was added to all test wells, and the mixture was incubated at room temperature for 60 minutes. Then, 5 μL of the reaction mixture was spotted on a phosphocellulose (Wattman, p81) filter, and the phosphorylated 32P-labeled peptide was adsorbed on the filter. Thereafter, the filter was washed three times with a 0.75% phosphoric acid solution to remove unreacted substances, and the reacted 32P was counted using BAS5000 (FUJIFILM).

[0175] The count value of "blank" (without enzyme) was set to 0%, and the count value of "total" (without enzyme) was set to 100%. Using these control values, the IC50 value of enzyme activity was determined. It was determined.

[0176] (3) Evaluation results

As a result of evaluating the compound according to the above-mentioned (2) Aurora 2 Kinase Atsushi procedure, it was confirmed that the compound of the formula (I) of the present invention inhibits Aurora 2 kinase activity. The results are shown in Table 2. In the column of “I-Danied Product” shown in Table 2, the compound numbers shown in Table 1 are shown.

[0177] [Table 2]

[0178] From these results, it was clarified that the conjugate shown in Examples of the present invention exhibited a potent Aurora 2 kinase activity inhibitory action.

Industrial applicability

[0179] According to the present invention, a novel aminobirimidine conjugate can be provided.

[0180] This application is a Japanese patent application filed on May 20, 2004 (Japanese Patent Application No. 2004-15).

0962), which is incorporated by reference in its entirety.

ll600 / S00Zdf / X3d IP OSSCll / SOOZ OAV

Claims

Claims The following formula (I)

[Chemical 1]

[Wherein, R ¹ and R ² are the same or different and represent a halogen atom, an alkyl, a hydroxy, an alkoxy, an aminoalkylamino or an acylamino,

R ⁵ represents a hydrogen atom, alkyl or acyl,

R ⁸ represents a ^{^{COR 10, CO R 10, CONR'V}} 1, CSNR ^ R 11, SO R 10 or OR ¹⁰ [wherein

twenty two

, R ^1C> and R ¹¹ may be the same or different—T—R ¹² {wherein T is absent or an atom of C

2-6 2-6

Ren, alkyl - A C (= 0) to three methylene from one of Ren, one C (= 0) 0, one OC (= 0) -, one C (= 0諫¹⁴⁾ one, OC (= ^{0) N (R 14) -} , one NR ¹⁴ -, one N (R ") 0 -, N (R 14) C (= 0) -, - N (R 14) C (= 0) 0 -, - N (R ¹⁴ ) C (= 0) N (R ¹⁵ ) —, S (0) —, NR

2

^{14 S (0) -, -} S (0) N (R 14) -, - N (R 14) C (NH) N (R 15) -, an oxygen atom or a sulfur atom

twenty two

(Wherein R ¹⁴ and R ¹⁵ are the same or different and represent hydrogen or alkyl), and R ¹² is hydrogen, a halogen atom, hydroxy, alkyl, alkyl having an amino group, Indicates a heterocycle or aryl. } Or R ^1C) and R ¹¹ represent a group that forms a 5- to 7-membered ring with the nitrogen atom bonded to each other. ], R ⁹ represents a hydrogen atom, a force indicating alkyl, hydroxy, alkoxy or acyl.R ⁸ represents OR ¹⁰ , R ⁹ represents a hydrogen atom, or

R ⁸ and R ⁹ each represent a group which forms a 5- to 7-membered ring together with a nitrogen atom bonded to each other. ], A pharmaceutically acceptable salt, hydrate, water adduct or solvate.

[2] In the above formula (I), R ³ and R ⁴ are the same or different and represent a hydrogen atom or alkyl;

R ⁸ is COR CONR'V ¹ , SO R ^1C) or OR (where R ^1C> and R ¹¹ are the same or

2

Different from T—R ¹² {wherein T is absent, C alkylene or its alkylene

1-6

R ⁹ represents a hydrogen atom, an alkyl or acyl group, or

R ⁸ and R ⁹ each represent a group forming a 5- to 7-membered ring together with a nitrogen atom bonded to each other, the compound according to claim 1, a pharmaceutically acceptable salt, a hydrate, a water adduct or a solvent. Japanese food.

[3] The compound according to claim 1 or 2, wherein R ¹ and R ^{2 in} formula (I) are the same or different and represent alkyl or acylamino, a pharmaceutically acceptable salt, hydrate or water adduct. Or a solvate.

[4] In the above formula (I), R ³ and R ⁴ each represent a hydrogen atom, the compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt, a hydrate, a water adduct or Solvate.

[5] The compound, pharmaceutically acceptable salt, hydrate, water adduct or solvate according to any one of claims 1 to 3, wherein in the formula (I), R ⁵ represents a hydrogen atom.

[6] In the formula (I), R ³ and R ⁴ each represent a hydrogen atom, and R ⁵ represents a hydrogen atom. The compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt, and water. Japanese products, water adducts or solvates.

[7] The prevention of cancer characterized by containing the aminovirimidine conjugate or the pharmaceutically acceptable salt, hydrate, water adduct or solvate thereof according to claim 1 to 6. And Z or treatment

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