WO2008053812A1 - Cyanopyridine derivative and medicinal use thereof - Google Patents

Abstract

Although several substances inhibiting Aurora kinase 2 have been reported, there has never been found out hitherto one having a sufficient biological activity in treating diseases. Thus, it is intended to provide an Aurora kinase 2 inhibitor which is useful in treating cell proliferative diseases typified by cancer. It is found out that a cyanopyridine compound represented by the following general formula (I), its pharmaceutically acceptable salt or a hydrate, a water adduct or a solvate of the same has a potent carcinostatic effect, thereby completing the invention.

Description

 Specification

 Cyanpyridine derivatives and their use as pharmaceuticals

 Technical field

 [0001] The present invention relates to a novel cyanopyridine derivative and a pharmaceutical comprising the same as an active ingredient.

 Background art

 [0002] Protein kinases are considered to be important drug targets along with GPCRs (G protein-coupled receptors). Abnormal activation of protein kinases has been associated with a number of diseases involving abnormal cell growth. For example, inflammatory and proliferative diseases, so-called tumors, rheumatoid arthritis, heart diseases, neurological diseases, psoriasis, asthma, hyperproliferation such as intravascular smooth muscle proliferation of stenosis or restenosis after angioplasty Obstacles. Protein kinase abnormalities are said to be directly and indirectly related to 400 human diseases. Therefore, if the activity of protein kinase can be manipulated, various diseases can be effectively treated. Power to do S There are only a few compounds on the market as pharmaceuticals (Non-patent Document 1).

 [0003] Protein phosphorylation is extremely important for the mitotic progression of cells that cause cancer and genetic diseases, and a series of serine / threonine kinases called mitotic protein kinases play this role. It has been revealed. Mitochondrial protein kinases phosphorylate various proteins at specific timings and locations to promote accurate cell division, but once their control is disrupted, there are a variety of chromosomes, including chromosome distribution. Abnormalities occur in mitotic events, resulting in large phenotypic changes in cells. One of these mitotic protein kinases is Aurora kinase. O Bite lakinase is a highly conserved serine / threonine kinase that is

It is considered to be an important enzyme for the progression of M phase because it is expressed in M phase. It is highly conserved from yeast to humans. Humans have homologues up to Aurora 1-3, and Aurora 2 kinase and Aurora 1 kinase are ubiquitous in various cells. Aurora 3 kinase is localized in the testis. Among them, the remains encoding Aurora 2 kinase The gene is located on the long arm of chromosome 20 and this region is associated with many cancers. Functional inhibition of the Aurora 2 kinase homologous gene using yeast, Drosophila, and nematodes also suggested the importance of this kinase family in the M phase (Non-patent document 2 and Non-patent document 3). The fact that Aurora 2 kinase is overexpressed in many cancers! /, (Non-patent document 4, Non-patent document 5, Non-patent document 6, Non-patent document 7, Non-patent document 8, Non-patent document 9 and Non-patent document Patent Document 10) and the fact that experimentally overexpressed Aurora 2 kinase in normal cells revealed that the cells showed signs of canceration (Non-Patent Document 11).

In addition, it was shown that treatment of human tumor cell lines with antisense oligonucleotide suppresses the expression of Aurora 2 kinase and suppresses cell proliferation (Patent Document 1). This is because it is possible to suppress the abnormal growth of cells by inhibiting the activity of Aurora 2 kinase, and it is considered useful for the treatment of many diseases accompanied by abnormal growth of cells such as cancer. It is done.

 Low molecular weight compounds that inhibit Aurora 2 kinase have been reported in patents! For example, Patent Literature 2, Patent Literature 3, Patent Literature 4, Patent Literature 5, Patent Literature 6, Patent Literature 7, Non-Patent Literature 12, Non-Patent Literature 13 and Non-Patent Literature 14 may be mentioned.

Patent Document 1: JP 2002-95479 A

Patent Document 2: Pamphlet of International Publication No. 2001-21595

Patent Document 3: Pamphlet of International Publication No. 2002-22601

Patent Document 4: International Publication No. 2002-66461 Pamphlet

Patent Document 5: Pamphlet of International Publication No. 2003-55491

Patent Document 6: International Publication No. 2005-013996 Pamphlet

Patent Document 7: US Patent Application Publication No. 2005-0256102

Non-patent literature l: Irena Melnikova et al., Nature Reviews / Drug Discovery, 3 993-994, 2004

Non-Patent Document 2: David M. Glover et al., Cell, 81 95-105, 1995

Non-patent literature 3: Daniela Berdnik et al., Current Biology, 12 640-647, 2002 Non-patent literature 4: Hongyi Zhou et al., Nature Genetics, 20 189-193, 1998 Non-patent literature 5: Takuji Tanaka et al. Cancer Research, 59, 2041-2044, 1999 Non-Patent Document 6: C. Sakakura et al., British Journal of Cancer, 84, 824-831, 2001 Non-Patent Document 7: Subrata Sen et al., Journal of the National Cancer Institute, 94, 1320-1329, 2002

 Non-Patent Document 8: Donghui Li et al., Clinical Cancer Research, Vol. 9, 991-997, 2003 Non-patent Document 9: Yung-Ming Jeng et al., Clinical Cancer Research, Vol. 206, 2065-2071, 20 04

 Non-Patent Document 10: Sangeeta Rojanala et al., Molecular Cancer Therapeutics Vol.3, No.4, 451-457, 2004

 Non-patent literature l l: James R. Bischoi¾, EMBO Journal, 17 3052-3065, 1998 Non-patent literature 12: Elizabeth A. Harrington et al., Nature Medicine 10 3 262-267, 2 004

 Non-patent document 13: Nicolas Keen et al., Nature Reviews Cancer 4, 927-936, 2004 Non-patent document 14: Daniele Faucelli et al., J. Med. Chem. 48, 3080-3084, 2005 Disclosure of the invention

 Problems to be solved by the invention

[0005] An object of the present invention is to provide a novel cyanopyridine derivative and a medicine containing the same as an active ingredient.

 Means for solving the problem

[0006] As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that the cyanopyridine derivative represented by the general formula (I), a pharmaceutically acceptable salt, hydrate, water adduct or solvate thereof. It was found that the product has a strong anticancer effect. The present invention has been completed based on the above findings.

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

 (1) General formula (I)

[0008] [Chemical 1]

R ^x

N 丄 .R ⁷ [Wherein, R ¹ represents the general formula (II) or the general formula (III).

[0010] [Chemical 2]

R ³ R ⁵ R ³

(ID R ⁴

[ooi i] (In the general formulas (π) and (in), ir, R ³ ′, R ⁵ and R ⁵ ′ are the same or different and each represents a hydrogen atom, a halogen atom or an optionally substituted alkyl. Alternatively, R ³ and R ³ ′ or R ⁵ and R ⁵ ′ may be joined together to form an oxo.

In the general formulas (II) and (III), X represents NR ⁶ or a sulfur atom. Here, R ⁶ represents a hydrogen atom or substituted! /, May! /, Alkyl.

 In general formulas (II) and (III), Y represents an oxygen atom or a sulfur atom.

 In the general formulas (II) and (III), n represents an integer of 1 to 5, and m represents an integer of 0 to 4.

In the general formula (II), when n represents an integer of 2 to 5, R ⁴ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, a substituted Represents! /, May! /, An aromatic heterocycle, substituted les, may! /, Alkoxycarbonyl, or an optionally substituted non-aromatic heterocycle. In the general formula (II), when n is 1, R ⁴ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted pyridylcarbonyl, an optionally substituted May be substituted, may be substituted! /, Urea or substituted! /, May! /, Cheurea.

In the general formula (III), when m represents an integer of 1 to 4, R ⁴ is a hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, substituted Is! /, May! /, Aromatic heterocycle, substituted les, may! /, Alkoxycarbonyl or substituted! /, May! /, Non-aromatic heterocycles.

In the general formula (III), when m represents 0, R ⁴ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted pyridylcarbonyl, or a substituted! /, Mayo! /, Asil, substituted! /, Mayo! /, Urea or substituted! /, Mayo! /, Tow. )

R ² represents a hydrogen atom, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted hydroxy. Rilalkyl, optionally substituted rubamoyl, optionally substituted alkanoylamino, substituted, may! /, Alkylamino or amino.

R ² ′ represents a hydrogen atom or substituted! /, May! /, Alkyl.

Alternatively, R ² and R ² ′ may be joined together to form an optionally substituted ring.

R ^x represents TR ⁸ . Here, T represents a valence bond or an alkylene chain, R ⁸ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted, an aromatic heterocyclic ring. Or substituted !, may! /, Represents a non-aromatic heterocycle.

R ⁷ represents a hydrogen atom, an optionally substituted alkyl or a halogen atom.

Alternatively, R ^X and R ⁷ may be taken together to form an optionally substituted ring. Or a pharmaceutically acceptable salt, hydrate, water adduct or solvate thereof.

 (2) —In general formula (I),

 T represents a valence bond,

R ⁸ represents an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted, an aromatic heterocycle or a substituted !, may! /, Non-aromatic heterocycle ,

When R ¹ represents the general formula (II) (n represents an integer of 2 to 5) or the general formula (III) (m represents an integer of 1 to 4), R ⁴ is substituted with a hydrogen atom, Optionally substituted alkyl, substituted, aryl, or substituted! /, May! /, Represents an aromatic heterocycle,

When R ¹ represents the general formula (II) (n represents 1) or the general formula (III) (m represents 0), R ⁴ may be substituted, may be! /, Alkyl or substituted /! Or even! /, A syranopyridine derivative, a pharmaceutically acceptable salt, hydrate, water adduct or solvate thereof according to (1), which represents aralkyl.

 (3) —In general formula (I),

R ⁸ is substituted! /, May! /, C alkyl, substituted! /, May! /, Phenyl, substituted

 14

, May! /, Pyridyl, substituted! /, May! /, Piperidinore or substituted! /, May! / ヽ

When R ¹ represents the general formula (II) (n represents an integer of 2 to 5) or the general formula (III) (m represents an integer of 1 to 4), R ⁴ is substituted! /, Maybe! /, C alkyl, substituted! /, Mayo! /, Phenyl, substituted les, may! /, Pyridyl or substituted! /, May! /, Pyrimidyl, R ¹ is represented by the general formula (II) (n represents 1) or general formula ( III) (m represents 0), R ⁴ represents an optionally substituted C alkyl or an optionally substituted C aralkyl.

 1—4 7- 14

 Show,

 The cyanopyridine derivative according to the above (1) or (2), a pharmaceutically acceptable salt, hydrate, water adduct or solvate thereof.

 (4) The prevention of cancer comprising the cyanopyridine derivative according to any one of (1) to (3) above, a pharmaceutically acceptable salt, hydrate, water adduct or solvate thereof as an active ingredient. And / or therapeutic agent.

 (5) Aurora containing as an active ingredient the above-mentioned (1) to (3)! /, The cyanopyridine derivative according to any one, or a pharmaceutically acceptable salt, hydrate, water adduct or solvate thereof 2 Kinase inhibitor.

 The invention's effect

 [0012] According to the present invention, a substance selected from the group consisting of a cyanopyridine derivative represented by the general formula (I), a pharmaceutically acceptable salt, hydrate, water adduct and solvate thereof is used as an active ingredient. It is possible to provide a medicine.

 BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

 [0014] Each substituent represented by the general formula (I) of the present invention is defined below.

In the present invention, as the substituent in “optionally substituted”, unless otherwise specified, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine), C alkyl (methyl)

 1-6

 Nole, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butynole, pentyl, hexyl, etc.), halo C anolenoquinoles (fluoromethyl, difluoromethyl, trimethyl)

 1 -6

 Fluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, etc.), cyan, nitro, hydroxy, C alkoxy (methoxy, ethoxy, propoxy, di)

 1 -6

 Soproboxy, butoxy, tert-butoxy, etc.), mercapto, C alkylthio (methylthio)

 1 -6

, Ethylthio, n-propylthio, isopropylthio, n-butylthio, etc.), amino, mono- or di-C alkylamino (methylamino, ethylamino, n-propylamino, isop Methyl pyramino, n-butylamino, dimethylamino, jetylamino, N-methyl-N-ethylamino, C alkanoylamino (acetylylamino, propionylamino, cyclopropyl)

 2- 7

 Carbonylamino, etc.) c alkylsulfonylamino (methanesulfonylamino, ethane)

 1 -6

 Sulfonylamino, etc.), 5- to 7-membered cyclic groups (eg, piperidyl, piperazil, pyrrolidinyl, morpholinyl, thiomorpholinyl, pyridyl, etc.), carboxyl, C alkoxy

 1 -6

 Norebonyl (methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), force norebamoyl, mono- or di-C alkyl one strength ruvamoyl (methylcarbamoyl,

 1-6

 Ethylcarbamoyl, cyclopropyl-powered rubermoyl, etc.), C alkanol (acetinore)

 2- 7

 , Propionyl, etc.). These substituents may be further substituted with the same or different one or more of the above substituents.

 In the present invention, “optionally substituted” means 1 to 5 (preferably 1 to 3) substituents at positions that can be substituted by any of the above-described substituents, unless otherwise specified. It is meant to include those with In addition, when there are a plurality of substituents, the types of the substituents may be the same or different! /, Or! /.

[0017] Examples of the "norogen atom" represented by R ³ ', R ⁵ and R ⁵ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a fluorine atom is particularly preferred.

[0018] Examples of the alkyl in the "optionally substituted alkyl" represented by R ³ , R ³ ', R ⁵ and R ⁵ include C alkyl (eg, methyl, ethyl, propyl, isopropyl).

 1 -6

 Straight chain or branched chain C alkyl such as pill, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl, and C cyclic alkyl such as cyclopropyl).

 1-6 3-6

 Preferably, it is C alkyl (eg, methyl, ethyl, propyl, isopropyl). This

 13

 When the alkyl is substituted, examples of the substituent include the same substituents as those described above.

[0019] Examples of the alkyl in the "optionally substituted alkyl" represented by R ⁶ include the same as the alkyl in the above "optionally substituted alkyl", and in particular, C alkyl ( Examples, methyl, ethyl, propyl) are preferred. The alkyl is

 13

 When it is substituted, examples of the substituent include the same as the above-described substituent.

[0020] As the alkyl in "substituted! /, May! /, Alkyl" represented by R ⁴ , Are the same as those in the “optionally substituted alkyl” represented by the above, and in particular, C alkyl (eg, methyl, ethyl, propyl, isopropyl, tert-butyl) is

 14

 preferable. When the alkyl is substituted, examples of the substituent include those similar to the above-mentioned substituent, and preferably a halogen atom, hydroxy, C alkoxy, amino and

 1 -6

 And a 5- to 7-membered cyclic group.

[0021] Examples of the alkenyl in the "optionally substituted alkenyl" represented by R ⁴ include C alkenyl such as bull. The alkenyl is substituted

 2-6

 In this case, examples of the substituent include the same substituents as those described above.

[0022] Examples of the "substituted! /, May! /, Aryl" represented by R ⁴ include C aryl such as phenyl, 1-naphthyl, 2-naphthyl, and the like, and is preferably phenyl. The phenyl is

 6-10

 When it is substituted, examples of the substituent include those similar to the above-mentioned substituent, and preferred are a halogen atom, cyano and C alkanoylamino.

 2- 7

[0023] The aromatic heterocycle in the "substituted! /, May! /, Aromatic heterocycle" represented by R ⁴ is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom Containing 1 or 2 heteroatoms;! To 4 5 to 10-membered monocyclic or bicyclic aromatic heterocycles (eg, phenyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, N- Oxopyridyl, pyrazinyl, pyrimigenole, thiazolyl, oxazolyl, triazolinole, benzocenyl, indolyl, quinazolyl, thieno [b] pyridyl, benzodioxol, etc.), preferably pyridyl, pyrajuryl, pyrimidyl, thieno [b] Pyridyl. When the aromatic heterocycle is substituted, examples of the substituent include those similar to the above-mentioned substituents, preferably a halogen atom, C alkyl, cyan, C alkylthio and C alkanoylamino.

 1 -6 1 -6 2-7

 It is.

[0024] The alkoxy power norlevonyl in "optionally substituted alkoxycarbonyl" represented by R ⁴ includes, for example, C alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like. The alkoxy power

 1-6

 When bonyl is substituted, examples of the substituent include those similar to the above-described substituent.

[0025] A non-aromatic heterocyclic ring in "substituted! /, May! /, Non-aromatic heterocyclic ring" represented by R ⁴ Examples thereof include 5- to 7-membered non-aromatic complex rings such as piperidyl, piperazil, morpholinyl and the like. When the non-aromatic heterocyclic ring is substituted, examples of the substituent include the same as the above-described substituent.

[0026] The aralkyl in “substituted! /, Mayo! /, Aralkyl” represented by R ⁴ is “substituted! /, May! /, Ariel” or “ Substituted! /, May! / Is a group formed by linking an “aryl” or “aromatic heterocycle” of an aromatic heterocyclic ring to a C alkyl,

 14

 For example, C aralkyl such as benzyl, phenethyl, pyridino remetinole, pyridylethyl, etc.

 7-14 etc. When the aralkyl is substituted, examples of the substituent include the same as the above-described substituent.

Examples of the acyl in the “optionally substituted acyl” represented by R ⁴ include C alkanoyl such as acetyl and bivaloyl. The isil is replaced

 2- 7

 In this case, examples of the substituent include the same substituents as those described above.

[0028] Examples of the alkyl in the "substituted! /, May! /, Alkyl" represented by R ² include those similar to the "alkyl" represented by the above, and in particular, C alkyl (eg, methyl ,

 13

 Til, propyl, isopropyl, cyclopropyl). When the alkyl is substituted, examples of the substituent include the same substituents as those described above.

[0029] Examples of alkoxy in "substituted! /, May! /, Alkoxy" represented by R ² include C alkoxy such as methoxy, ethoxy, isopropoxy and the like. The alkoxy is

 1 -6

 When it is substituted, examples of the substituent include the same as the above-described substituent.

Examples of the alkylthio in the “substituted! /, May! /, Alkylthio” represented by R ² include those in which the alkyl moiety is the same as the “alkyl” represented by R ³ , for example, And C alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, cyclopropylthio, and butylthio. The alkylthio is substituted

 1 -6

 In this case, examples of the substituent include the same as those described above.

[0031] Examples of the hydroxyalkyl in the "optionally substituted hydroxyalkyl" represented by R ² include hydroxy C alkyl such as hydroxymethyl and hydroxyethyl.

 1 -6

I can get lost. When the hydroxyalkyl is substituted, examples of the substituent include the same as the above-described substituent. [0032] “Substituted! /, May! /, Rubamoyl” represented by R ² includes rubamoyl, mono- or di-C alkyl rubamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.)

 1 -6

 And the like.

[0033] Examples of the alkanoylamino in the "substituted! /, Mayo! /, Alkanoylamino" represented by R ² include C alkanoylamino and the like such as acetylamino and bivalloamino.

 2- 7

 The When the alkanoylamino is substituted, examples of the substituent include those similar to the above-described substituent.

[0034] The alkylamino in "substituted! /, May! /, Alkylamino" represented by R ² may be either mono- or di-alkylamino, such as methylamino, ethylamino, isopropylamino, dimethylamino. , Jetilamino etc. Mono or G

 1-6 alkylamino and the like. When the alkylamino is substituted, examples of the substituent include the same substituents as those described above.

[0035] As "alkyl which may be substituted" represented by R ^2, the represented by R ³ 'is replaced! /, I be! / Alkyl "include the same.

[0036] The ring in the "optionally substituted ring" formed by R ² and R ² 'together is particularly preferably a 5- to 10-membered monocyclic or bicyclic ring such as a benzene ring , Pyridine ring, pyrimidine ring

, Indole ring, pyrrolidine ring, piperidine ring, morpholine ring, homopiperidine ring, tetrahydrothiophene ring and the like. When the ring is substituted, examples of the substituent include the same as the substituent.

[0037] The "alkylene chain" represented by T is, for example, a C 4 linear or branched saturated hydrocarbon.

 14

 Divalent group derived from silicon, specifically, C-alkyl such as methylene, ethylene, propylene, etc.

 1-6 Lucylene and the like.

[0038] Examples of the alkyl in the "substituted! /, May! /, Alkyl" represented by R ⁸ include the same as the alkyl in the "optionally substituted alkyl" represented by the above. C alkynoles such as methyl, ethyl, propyl, isopropyl, cyclopropyl, etc.

 1 -4 force S is preferable. When the alkyl is substituted, examples of the substituent include the same ones as the above-mentioned substituent, preferably a halogen atom and a 5- to 7-membered cyclic group.

[0039] The Ariru in the "optionally substituted Ariru" represented by R ^8, at the R ⁴ Examples thereof are the same as those shown in the “optionally substituted aryl” shown below, and preferably phenyl. When the aryl is substituted, examples of the substituent include those similar to the above-mentioned substituent, and preferably C alkoxy.

 1 -6

[0040] represented by R ⁸ 'is substituted! /, Even I! /, Aromatic heterocyclic ring "aromatic heterocyclic ring in the" aromatic substituted represented by R ⁴ complex Examples of the aromatic heterocyclic ring in the “ring” include the same, and preferred are pyridyl, chenyl, and benzodioxol. When the aromatic heterocycle is substituted, examples of the substituent include those similar to the above-mentioned substituent, and preferably C alkyl.

 1 -6

[0041] The non-aromatic heterocycle in the "substituted! /, May! /, Non-aromatic heterocycle" represented by R ⁸ includes a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom. 1 to 2 of 1 to 2 heteroatoms selected from 5 to; 10-membered monocyclic or bicyclic non-aromatic heterocycles (eg piperidinole, piperazil, pyrrolidinyl, monomorpholinole, thiomorpholinyl) Etc.), preferably piperidyl. When the non-aromatic heterocycle is substituted, examples of the substituent include those similar to the above-mentioned substituent, preferably carboxyl and C

 1-6 Norecoxy carbonyl.

[0042] Examples of the alkyl in the "substituted! /, May! /, Alkyl" represented by R ⁷ include the same as the alkyl in the "optionally substituted alkyl" represented by the above. In particular, C alkyl (eg, methyl etc.) is preferred. When the alkyl is substituted

 13

 In addition, examples of the substituent include the same substituents as those described above.

[0043] As "Nono androgenic atom" represented by R ⁷ is, include those similar to the "Nono androgenic atom" represented by R ^3, in particular, a fluorine atom, a chlorine atom is preferable.

[0044] The ring in the “optionally substituted ring” formed by R ^x and R ⁷ being joined together includes 5

-7 membered ring is mentioned, for example, a cyclopentane ring, a cyclohexane ring, etc. are mentioned. When the ring is substituted, examples of the substituent include the same substituents as those described above.

 [0045] Examples of the pharmaceutically acceptable salt in the compound of the general formula (I) include acid addition salts with inorganic acids or organic acids.

[0046] Pharmaceutically acceptable salts in the compounds of general formula (I) include water adducts, hydrates and solutions. These water adducts, hydrates and solvates are also encompassed by the present invention as they may exist as solvates.

[0047] Optically active substances in the compound of the general formula (I) are also included in the present invention.

[0048] The compound of the present invention contained in the general formula (I) can be synthesized by the following method.

[0049] In the following reaction formula, the definition of each symbol is as defined above unless otherwise specified.

[0050] [Chemical 3]

[0051] The raw material for producing the compound of the present invention represented by the general formula (I) is represented by the general formula (IV) (in the general formula (IV), L represents a fluorine atom, a chlorine atom or a bromine atom). 2,6-dihaguchi-3-cyanobilidine derivatives are used.

[0052] This starting compound can be produced by a known method (J. Org. Chem. Vol. 25 p560, JP-A-49-62477, Bioorg. Med. Chem. Lett. 11 (2001). ) ρ475, J.Org.Chem.44 (1979) p2693) ₀ or the corresponding β-ketoester is reacted with 2-cyanoacetamide in the presence of DBU (diazabicyclo [5,4,0] undecene), The precipitate can be easily synthesized by heat treatment with phenylphosphonic dichloride.

 [0053] In reaction 1, the compound of general formula (IV) and the 3-aminobiazole derivative are placed in a suitable solvent at room temperature or under heating in the presence of a base to obtain a compound of formula (V). This force S is possible. Alternatively, when no base is present, the reaction proceeds thermally by increasing the reaction temperature, whereby compound (V) can be obtained.

[0054] The above base is not particularly limited as long as it is a substance for accelerating the reaction, metal alkoxide such as tertiary amine, potassium tert-butoxide, diazabicyclo [5,4,0] un Examples thereof include amidines such as decene, metal hydrides such as guanidine and sodium hydride, metal fluorides such as potassium fluoride, and solids carrying metal fluorides. In particular, tertiary amine (triethylamine, Huech base) is preferred.

[0055] The amount of the base to be added is usually 0.;! To 30 equivalents, preferably 1 to 10 equivalents based on the compound.

 [0056] The solvent used in the reaction is not limited as long as it does not inhibit this reaction. Mentioning oxan, N, N-dimethylformamide (hereinafter referred to as DMF).

[0057] The reaction temperature of this reaction is usually 20 ° C to 200 ° C, preferably 80 ° C to 150 ° C.

[0058] The reaction time varies depending on the temperature or the type of solvent and is usually 30 minutes to 8 hours.

[0059] The reaction proceeds similarly in the compound in which the pyrazole nitrogen of the 3-aminobiazole derivative is protected with a general protecting group, and the corresponding protected form of formula (V) is obtained. The compound of formula (V) can also be obtained by protection.

 [0060] Examples of the protecting group include trityl, benzyloxymethyl, ethoxymethyl, and benzyloxycarbonyl.

 [0061] After completion of the above reaction, the target product of each reaction can be collected from the reaction mixture according to a conventional method. For example, by concentrating the reaction mixture, or if solids are present, the solids are removed by appropriate filtration, and then the liquid is crystallized by adding it to basic or neutral water for crystallization. Things are obtained. If the target product does not crystallize, wash it with an organic solvent immiscible with water, such as ethyl acetate or black mouth form, separate the organic layer containing the target product, dry it over anhydrous magnesium sulfate, etc., and then evaporate the solvent. It is obtained by doing.

[0062] If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation, washing with a solvent, or chromatography.

[0063] In reaction 2, the compound of formula (I) can be obtained by heating the compound of general formula (V) and the amine derivative or thiol derivative in the presence of a base in an appropriate solvent.

. Alternatively, in the absence of a base, the reaction can be accelerated thermally by increasing the reaction temperature, thereby obtaining the compound (I). [0064] The base is not particularly limited as long as it is a substance for accelerating the reaction, metal alkoxide such as tertiary amine, potassium tert-butoxide, diazabicyclo [5,4,0] undecene, etc. Examples include metal hydrides such as amidine, guanidine, sodium hydride, sodium hydrogen carbonate, and the like. In particular, sodium hydrogen carbonate is preferable.

 [0065] The amount of the base to be added is usually 0.;! To 30 equivalents, preferably 1 to 10 equivalents.

 [0066] The solvent used in the reaction is not limited as long as it does not inhibit this reaction, but preferably THF, DMSO, 1,4-dioxane, DMF and the like can be mentioned.

 The reaction temperature of this reaction is usually 60 ° C to 200 ° C, preferably 80 ° C to 150 ° C.

[0067] The reaction time varies depending on the temperature or the type of solvent, and is usually 1 to 100 hours.

 [0068] In the compound of the general formula (V) in which the pyrazole nitrogen is protected with a general protecting group, the reaction proceeds in the same manner to obtain the corresponding protected product of the formula (I). By deprotection, a compound of formula (I) can also be obtained.

 [0069] After completion of the above reaction, the target product of each reaction can be collected from the reaction mixture according to a conventional method. For example, the reaction mixture is concentrated, and if a solid is present, the solid is removed by filtration as appropriate, and then the liquid is added to water for crystallization to obtain the desired product. If the target product does not crystallize, wash it with an organic solvent immiscible with water, such as ethyl acetate or chloroform, separate the organic layer containing the target product, dry it over anhydrous magnesium sulfate, etc. It is obtained by leaving.

 [0070] The thus-produced cyanopyridine derivative of the general formula (I) of the present invention is appropriately subjected to known separation and purification means, for example, means such as concentration, extraction, chromatography, reprecipitation, recrystallization and the like. By applying, it can be collected as having an arbitrary purity.

 [0071] The salt, hydrate, water adduct and solvate of the cyanopyridine derivative represented by the general formula (I) can be produced from the cyanopyridine derivative by a known method.

[0072] The compound of the general formula (I) obtained by the above method, or a pharmaceutically acceptable salt, hydrate, water adduct and solvate thereof have anticancer activity, and Or it is useful as a therapeutic agent. [0073] The compound of the present invention, optical isomers thereof or pharmaceutically acceptable salts thereof can be safely used with low toxicity. The dosage can be appropriately determined depending on conditions such as the patient's age, health condition, weight, etc., and if there are drugs to be administered at the same time, conditions such as the type and frequency of administration, or the nature of the desired effect. . In general, the daily dose of active ingredient is 0.5 to 300 mg / kg body weight, usually;! To 30 mg / kg body weight, and can be administered one or more times per day.

 [0074] When the compound of the present invention is used as a medicine, a pharmaceutical composition containing the above active ingredient and one or more pharmaceutically acceptable excipients for preparation is prepared and administered. It is preferable.

 [0075] Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, liquids, elixirs and the like. Examples of the pharmaceutical composition suitable for parenteral administration include liquids. Alternatively, a sterilized liquid pharmaceutical composition such as a suspending agent can be exemplified.

 [0076] The type of pharmaceutically acceptable pharmaceutical additive used for the preparation of the pharmaceutical composition is not particularly limited, and an appropriate pharmaceutical additive is selected depending on the form of various pharmaceutical compositions. Is possible. The additive for the preparation may be either solid or liquid. For example, a solid carrier or a liquid carrier can be used. As an example of the solid carrier, an ordinary gelatin type capsule can be used. In addition, for example, the active ingredient can be tableted with one or two or more pharmaceutical additives, or without using pharmaceutical additives, or can be prepared and packaged as a powder. These capsules, tablets and powders can generally contain 5 to 95% by weight, preferably 5 to 90% by weight, of the active ingredient relative to the total weight of the formulation, and the dosage unit form is 5 to 500 mg. Preferably, it contains 25 to 250 mg of active ingredient. As the liquid carrier, water, oils of animal or vegetable origin such as petroleum, peanut oil, soybean oil, mineral oil, sesame oil or synthetic oils are used.

[0077] In addition, generally, there are physiological saline and dextrol! /, And similar sucrose solutions, glycols such as ethylene glycol, propylene glycol, and polyethylene glycol are preferable as the liquid carrier, and physiological saline is particularly used. In the case of injection solutions, it can be prepared so as to contain usually 0.5 to 20% by weight, preferably 1 to 10% by weight of the active ingredient. Example

 [0078] The present invention will be described more specifically with reference to examples and pharmacological experimental examples, but the present invention is not limited to these descriptions.

[0079] For chemical shift of ^ -NMR, tetramethylsilane (TMS) was used as an internal standard, and relative delta (δ) values were expressed in parts per million (ppm). The couplings are s (vlet), d (doublet), t (triplet), m (manolecchi)

 And brs (broad singlet). Thin layer chromatography was performed using Merck, and force ram chromatography was performed using silica gel manufactured by Fuji Silysia Chemical.

[0080] For the drying of the organic solution in the extraction, anhydrous sodium sulfate or anhydrous magnesium sulfate was used unless otherwise specified.

 (Reference Example 1)

[0081] [Chemical 4]

„ _Un ,, TsCl (l.Oeq) QTs

V ^M 35% H2S04aq HO | V ^Π DMAP (l.leq) HO, ''

 , -5 ° C, lday CH2C12 '

 yield.53% r.t. 26h

 A β yield. 23%

NaN3 (Jeq) HO, | 'f ³

[0082] [Synthesis of (6R) -2-methyl-heptane-2,6-diol (B)]

 Ingredients: (2R) -6-methyl-hept-5-en-2-ol (A) 35% sulfuric acid aqueous solution (19 ml) was added to (2.06 g) and left at -5 ° C for 17.5 hours did. The reaction system gradually became uniform from two layers. This was neutralized by pouring it into an ice bath containing sodium hydroxide (9.6 g). The target compound (B) (1.24 g, yield 53%) was obtained from this aqueous solution by six extraction operations with chloroform.

 [0083] [Synthesis of Toluene-4-sulfonic acid (1R) -5-hydroxy-1,5-dimethyl-hexyl ester (C)]

Compound (B) (0.95 g: 6. 50 mmol) was rapidly dissolved in salt methylene (10 ml), and DMAP (874 mg: 7. 15 mmol) and tosilk mouthride (1 · 24 g) were added. And allowed to react at room temperature for 26 hours. This This was washed with water, the organic layer was concentrated, and purified by silica gel column chromatography to obtain compound (C) (442 mg, yield 23%).

 [0084] [Synthesis of (6S) -6-azido-2-methyl-heptan-2-ol (D)]

 NaN (477 mg) was added to a DMF (4 ml) solution of compound (C) (440 mg: l.46 mmol), 80. C

 Three

 And reacted for 3.5 hours. After allowing to cool, the mixture was poured into water, extracted with ethyl acetate, washed with saturated brine, and concentrated to obtain compound) (222 mg, yield 89%).

 [0085] [Synthesis of (6S) -6-Amino-2-methyl-heptan-2-ol (E)]

 A catalytic amount of palladium hydroxide was added to a methanol solution of compound) (220 mg), and hydrogenated for 3.5 hours at room temperature. The reaction system was filtered through Celite to obtain compound) (146 mg, yield 78%).

[0086] [Chemical 5]

 Comp.1

 [0087] (Example 1)

 [2-((IS) -5-hydroxy-1,5-dimethyl-hexylamino) -4-methyl-6- (5_methyl-1H-pyrazole-3-ylamino) -nicotinonitryl (compound 1) Composition]

 2-black mouth-4-methyl-6- (5_methyl-1H-pyrazole-3-ylamino) -nicotinonitryl (F) (124mg: 0.50mmol), compound (E) (146mg: l. Olmmol) A solution of sodium bicarbonate (420 mg: 5 mmol) in DMSO (2 ml) was stirred with heating at 130 ° C for 6 hours. The reaction system was returned to room temperature and poured into water. This was extracted with ethyl acetate, washed with saturated brine, dried and concentrated. This was converted into a hydrochloride and crystallized with ethyl acetate: ethanol = 3: 1 to obtain the target compound l (35 mg).

[0088] (Reference Example 2)

[Synthesis of 3- (pyrimidine- ^2- yloxy) -propylamine]

Sodium hydride (1.26 g: 31.5 mmol) was added to a DMF solution of (3-hydroxy-propyl) -carbamic acid tert-butyl ester (5.4 g: 31.5 mmol) under ice cooling. To this was added 2-bromopyrimidine (5 g: 31.5 mmol), and the mixture was stirred at 120 ° C. for 14 hours. Saturate reaction system Poured into aqueous ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried and concentrated to (3- (pyrimidine-2-yloxy) -propyl) -force rubamic acid tert-butyl ester ( 4. 33 g) were obtained. This was treated with 2M-HC1 in dioxane and concentrated to give the desired 3- (pyrimidine-2-yloxy) -propylamine (4.33 g).

[Example 2]

 [Synthesis of 4-methyl-6- (5_methyl-1H-pyrazole-3-ylamino) -2- (3_ (pyrimidine-2-yloxy) -propylamino) -nicotinonitryl (compound 2)]

 2-Chloro-4-methyl-6- (5_methyl-1H-pyrazole-3-ylamino) -nicotinonitryl (F) (3. Og: l. 22 mmol), 3- (pyrimidine-2-yloxy) A DMSO solution of -propylamine (827 mg) and sodium hydrogen carbonate (1.0 g: 12.2 mmol) was heated and stirred at 130 ° C for 18 hours. The reaction system was returned to room temperature and poured into water. This was extracted with ethyl acetate, washed with saturated brine, dried and concentrated. This was converted to a hydrochloride and crystallized from ethanol to obtain the target compound 2 (1.42 g).

[0090] (Reference Example 3)

 [Synthesis of 7-mercapto-2-methyl-heptane-2-ol]

 To a THF solution of 6-bromo-hexanoic acid ethyl ester (3.69 g: 16.5 mmol) was added potassium thioacetate (2 g: 17.4 mmol), and the mixture was stirred for 21 hours. This was poured into cold water and extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography to obtain 6-acetylsulfanyl-ethyl acetate ester (1.17 g). This was dissolved in THF, treated with methylmagnesium bromide under ice cooling, and poured into cold water. This was extracted with ethyl acetate to obtain 7-mercapto-2-methyl-heptan-2-ol (990 mg).

[0091] (Example 3)

 [Synthesis of 2- (6_hydroxy-6-methyl-heptylsulfanyl) -4-methyl-6- (5_methyl-1H-virazol-3-ylamino) -nicotinonitryl (compound 3)]

2-black mouth-4-methyl-6- (5_methyl-1H-pyrazole-3-ylamino) -nicotinonitryl (F) (252 mg: l. 03 mmol), 7_mercapto-2-methyl-heptane-2 -A DMSO solution of ol (990 mg) and sodium hydrogen carbonate (1.0 g: 12.2 mmol) was heated and stirred at 130 ° C for 26 hours. It was. The reaction system was returned to room temperature and poured into water. This was extracted with ethyl acetate, washed with saturated brine, dried and concentrated. This was converted to a hydrochloride with 2Μ_ΗΟΕΐΟΗ and crystallized with acetonitrile-ethanol to obtain the target compound 3 (104 mg).

[0092] (Example 4)

 [Synthesis of 2- (2-Isopropoxy-ethylamino) -4-methyl-6- (5_methyl-1H-pyrazole-3-ylamino) -nicotinonitryl (Compound 4)]

 2-black mouth-4-methyl-6- (5_methyl-1H-pyrazole-3-ylamino) -nicotinonitryl (F) (10 g: 40.7 mmol), 2-isopropyloxy-ethylamine (10 mL), A DMSO solution of sodium hydrogen carbonate (34 g: 405 mmol) was heated and stirred at 130 ° C for 7 hours. The reaction system was returned to room temperature and poured into water. This was extracted with ethyl acetate, washed with saturated brine, dried and concentrated. This was recrystallized with ethyl acetate to obtain the target compound 4 (8. 79 g). This was converted into a hydrochloride with 2M-HC to EtOH.

[0093] (Reference Example 4)

 [Synthesis of 3- (pyridine-3-yloxy) -propane-1-thiol]

 To a THF (lOOmL) solution of pyridin-3-ol (5g), 3-bromo-propan-1-ol (11.4mL), triphenylphosphine (34.4g) in toluene (½0mL) of azodicarboxylate diethyl toluene. did. The mixture was stirred for 4 days, and the reaction solution was concentrated. This was separated with ethyl acetate-1M hydrochloric acid, and the aqueous layer was neutralized and extracted with ethyl acetate. The organic layer was washed with saturated Japanese salt water, dried and concentrated. The residue was purified by silica gel chromatography to obtain 3- (3_bromo-propoxy) -pyridine (9 · Og). This was dissolved in DMF, 18-crown-6-ether (3.3 g) and potassium thioacetate (5.3 g) were added and stirred for 5 days. This was poured into cold water, extracted with ethyl acetate and concentrated. The residue was purified by silica gel chromatography to obtain thioacetic acid S_ (3- (pyridine-3-yloxy) -propyl) ester (6.43 g). Next, 2 g of this was dissolved in methanol, treated with 1.2 mL of pyrrolidine for 17 hours, the reaction mixture was concentrated and purified by silica gel column chromatography to obtain the target 3- (pyridine-3-yloxy). ) -Propane-1-thiol was obtained.

[Example 5]

[4-Methyl-6- (5_methyl-1H-pyrazole-3-ylamino) -2- (3_ (pyridine-3-yloxy) ) -Propylsulfanyl) -nicotinonitryl (Compound 5)]

 2-Chloro-4-methyl-6- (5_methyl-1H-pyrazole-3-ylamino) -nicotinonitryl (F) (300 mg), 3- (pyridine-3-yloxy) -propane-1-thiol (619 mg) and a DMSO solution of sodium hydrogen carbonate (1. Og: 12.2 mmol) were heated and stirred at 130 ° C for 10.5 hours. The reaction system was returned to room temperature and poured into water. This was extracted with ethyl acetate, washed with saturated brine, dried and concentrated. This was recrystallized with ethyl acetate to obtain the target compound 5. In addition, this was converted to hydrochloride (136 mg) with 2M-HC to EtOH.

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 [0135] Pharmacological experiment example 1 Aurora 2 kinase activity inhibitory action

 (1) Preparation of Aurora 2 kinase

 Total RNA was extracted from HeLa cells (ATCC No. CCL-2) according to a conventional method, and cDNA was synthesized by reverse transcriptase reaction. PCR was performed using the cDNA as a saddle. The primer sequences used for the PCR reaction were SEQ ID NO: 1 (5, -GGA ATT CCA TAT GGA CCG ATC TAA AGA AAA CTG-3,) and SEQ ID NO: 2 (5,-GGG GGG CTC GAG AGA CTG TTT G CT AGC TGA TTC -3 ').

[0136] The sequence obtained by the PCR reaction is identical to the sequence of the aurora 2-kinase-encoding gene reported in the literature cited earlier (The EMBO Journal Vol. 17 No. 11 3052-3065 1998). there were.

 [0137] The amplified Aurora 2-kinase-encoding gene was introduced into the E. coli expression vector 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 In c.) ”You can get power S.

 [0138] Thereafter, the recombinant was introduced into Escherichia coli BL21R strain (Novagen) for mass expression of protein to produce Escherichia coli strain for aurora 2 kinase mass expression.

[0139] An E. coli strain for aurora 2 kinase large expression was cultured in an LB medium containing Ampicilin ^ O g / ml). Incubate Aurora 2 kinase after 1 hour shaking culture at 37 ° C For this purpose, the culture temperature was set to 25 ° C., a final concentration of 0. ImM IPTG (SIGMA) was added, and the cells were cultured with shaking at 25 ° C. for 24 hours. Thereafter, the culture solution was centrifuged at 7000 rpm for 10 minutes, and the cells were collected.

 [0140] The collected bacterial cells were treated with 36 ml of lysis buffer [50 mM Tris pH6.8, 150 mM NaCl, 20 mM β-Glycerophosphate, 0.3 mM Na V0, 50 mM NaF, 2 mM PMSF (phenylmethyl fluoride)

 3 4

 Sulfonyl), protease inhibitor cocktail tablet (Boehringer Mannheim) 1 tablet] and sonicated. Furthermore, 4 ml of 10% NP-40 (Wako Pure Chemical Industries) was added to dissociate nonspecific binding between proteins.

 [0141] After that, the recombinant Aurora 2 kinase in the solution was adsorbed onto N-to-NTA agarose beads (QIAGEN), and the beads adsorbed with the recombinant Aurora 2 kinase were mixed with 50 ml of K buffer (1M C1 / lxTNT), G buffer. Aurora 2 kinase was obtained by washing with (30% Glycerol, 0.5M KCl / lxTNT).

 [0142] (2) Aurora 2-kinase atsey

 Each well contains an enzyme reaction buffer (200 mM Tris-HCl (pH 7.0), lOOmM MgCl 2) (1.5 μ 1), 50 mM dithiothreitol (1.5 1), ImM peptide substrate [LRRASLG] (1 · 5 β 1), water (2.5 1), and DMSO solution with compound added (1.5 μ 1) were added.

 [0143] Aurora 2 kinase (lmg / ml, 1.5 1) diluted in enzyme diluent [50 mM Tris_HCl (pH 6.8), 200 mM NaCl, 50% glycerol, lmg / ml BSA] Added to all but wells. Enzyme Diluent 1.51 without Aurora 2 kinase was added to the “Blank” well. To the “total” well, DMSO solution containing no compound was added 1.5 H 1 calorie.

[0144] Next, 5 μ 1 of 28 HM ATP solution containing 1.2 Ci [( _y - ³² P) ATP (Muromachi Pharmaceutical, specific activity> 3500 Ci / m mol)] was added to all test wells The mixture was incubated at room temperature for 60 minutes, 5 μl of the reaction mixture was spotted on a phosphocellulose (Wattman, p81) filter, and the phosphorylated ³² P-labeled peptide was adsorbed on the filter. Thereafter, the filter was washed 4 times with 0.75% phosphoric acid solution to remove unreacted substances, and reacted ³² P was counted using BAS5000 (FUJI FILM).

[0145] The count value of “blank” (no enzyme) is 0%, and the count value of “total” (no compound) is 100 These control values were used as%, and the Ki value of enzyme inhibition activity was determined.

[0146] (3) Evaluation results

 As a result of evaluating the compounds according to the procedure of (2) Aurora 2 kinase assay described above, it was found that the compound of the formula (I) of the present invention inhibits Aurora 2 kinase activity.

[0147] From these results, it was revealed that the compounds shown in the examples of the present invention exhibited a potent inhibitory activity on Aurora 2 kinase activity.

[0148] [Table 41]

 Industrial applicability

 According to the present invention, it is possible to provide a cancer therapeutic agent comprising as an active ingredient a substance selected from the group consisting of a novel cyanopyridine derivative, a pharmaceutically acceptable salt, hydrate, water adduct and solvate thereof. it can.

 This application is based on Japanese Patent Application No. 2006-293151 filed in Japan, the contents of which are incorporated in full herein. In addition, patent documents and non-patent documents cited in the present specification are incorporated in the present specification to the same extent as the entire contents of the cited documents are disclosed.

Claims

Claim General Formula (I) [Chemical 1]

[Wherein R ¹ represents the general formula (II) or the general formula (III). [Chemical 2]

(In the general formulas (II) and (III), R ³ , R ³ ′, R ⁵ and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom or an optionally substituted alkyl, or R ³ and R ³ ′ or R ⁵ and R ⁵ ′ may be joined together to form an oxo. In the general formulas (II) and (III), X represents NR ⁶ or a sulfur atom. Here, R ⁶ represents a hydrogen atom or substituted! /, May! /, Alkyl. In general formulas (II) and (III), Y represents an oxygen atom or a sulfur atom. In the general formulas (II) and (III), n represents an integer of 1 to 5, and m represents an integer of 0 to 4. In the general formula (II), when n represents an integer of 2 to 5, R ⁴ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, a substituted Represents! /, May! /, An aromatic heterocycle, substituted les, may! /, Alkoxycarbonyl, or an optionally substituted non-aromatic heterocycle. In the general formula (II), when n is 1, R ⁴ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted pyridylcarbonyl, an optionally substituted Indicates a good acyl, may be substituted! /, Urea or substituted! /, May! /, Cheurea. In the general formula (III), when m represents an integer of 1 to 4, R ⁴ is a hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, substituted Is! /, May! /, Aromatic heterocycle, substituted les, may! /, Alkoxycarbonyl or substituted! /, May! /, Non-aromatic heterocycles. In the general formula (III), when m represents 0, R ⁴ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted pyridylcarbonyl, or a substituted! /, Mayo! /, Asil, substituted! /, Mayo! /, Urea or substituted! /, Mayo! /, Tow. ) R ² represents a hydrogen atom, hydroxy, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkylthio, an optionally substituted hydroxyalkyl, an optionally substituted force. Rubamoyl, optionally substituted alkanoylamino, substituted les, optionally! /, Alkylamino or amino. R ² ′ represents a hydrogen atom or substituted! /, May! /, Alkyl. Alternatively, R ² and R ² ′ may be joined together to form an optionally substituted ring. R ^X represents TR ⁸ Here, T represents a valence bond or an alkylene chain, R ⁸ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted, an aromatic heterocyclic ring. Or substituted !, may! /, Represents a non-aromatic heterocycle. R ⁷ represents a hydrogen atom, an optionally substituted alkyl or a halogen atom. Alternatively, R ^X and R ⁷ may be taken together to form an optionally substituted ring. Or a pharmaceutically acceptable salt, hydrate, water adduct or solvate thereof.  In general formula (I), T represents a valence bond, R ⁸ represents an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted, an aromatic heterocycle or a substituted !, may! /, Non-aromatic heterocycle , When R ¹ represents the general formula (II) (n represents an integer of 2 to 5) or the general formula (III) (m represents an integer of 1 to 4), R ⁴ is substituted with a hydrogen atom, Optionally substituted alkyl, substituted, aryl, or substituted! /, May! /, Represents an aromatic heterocycle, When R ¹ represents the general formula (II) (n represents 1) or the general formula (III) (m represents 0), R ⁴ may be substituted, may! /, Alkyl or substituted 2. The cyanopyridine derivative according to claim 1 or a pharmaceutically acceptable salt, hydrate, water adduct or solvate thereof, which indicates aralkyl. [3] In general formula (I), R ⁸ is substituted! /, May! /, C alkyl, substituted! /, May! /, Phenyl, substituted  14  , May! /, Pyridyl, substituted! /, May! /, Piperidinore or substituted! /, May! / ヽ When R ¹ represents the general formula (II) (n represents an integer of 2 to 5) or the general formula (III) (m represents an integer of 1 to 4), R ⁴ is substituted! /, Maybe! /, C alkyl, substituted! /, Mayo! /,  1-4 Phenyl, substituted les, may! /, Pyridyl or substituted! /, May! /, Pyrimidyl, R ¹ is represented by the general formula (II) (n represents 1) or general formula ( III) (m represents 0), R ⁴ represents an optionally substituted C alkyl or an optionally substituted C aralkyl.  1—4 7- 14  Show,  The cyanopyridine derivative according to claim 1 or 2, a pharmaceutically acceptable salt, hydrate, water adduct or solvate thereof. [4] A prophylactic and / or therapeutic agent for cancer comprising, as an active ingredient, the cyanopyridine derivative according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, hydrate, water adduct or solvate thereof. .  [5] An aurora 2 kinase inhibitor comprising the cyanopyridine derivative according to any one of claims 1 to 3 and a pharmaceutically acceptable salt, hydrate, water adduct or solvate thereof as an active ingredient.