JP2005089352A - NEW IMIDAZO[1,5-a]PYRAZINE DERIVATIVE, MEDICINE COMPOSITION CONTAINING THE SAME AND THEIR USE - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new compound that has strong inhibition activity against protein tyrosine kinase, especially Src family kinase and is useful as a medicine. <P>SOLUTION: The compound is represented by general formula (I) (R<SP>1</SP>is hydrogen or a lower alkyl; R<SP>2</SP>is hydrogen, a lower alkyl, a hydroxy lower alkyl or a lower acyl; R<SP>3</SP>and R<SP>4</SP>are each independently hydrogen, a halogen, a lower alkyl, a phenyl group which may be substituted or a heteroaryl group; R<SP>5</SP>is a phenyl group which may be substituted, a heteroaryl group or an aralkyl group), its prodrug or its pharmaceutically permissible salt. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a novel imidazo [1,5-a] pyrazine derivative having a protein tyrosine kinase inhibitory action, particularly an Src family kinase inhibitory action, a pharmaceutical composition containing the same, and uses thereof.

  Protein tyrosine kinases are enzymes that catalyze phosphorylation of specific tyrosine residues of cellular proteins, and play an important role in the regulation of cell activation, proliferation, and differentiation (see, for example, Non-Patent Document 1). Abnormal expression, stimulation or mutation of this protein tyrosine kinase is believed to lead to various diseases.

  Src family kinases are one of the non-receptor protein tyrosine kinases. Eight kinases (Src, Yes, Fyn, Fgr, Blk, Lck, Lyn and Hck) have been discovered as members of Src family kinases. Src family kinases are highly regulated in normal cells and are maintained in an inactive conformation in the absence of extracellular stimuli.

  Src is activated in many human cancers. For example, breast cancer (for example, see Non-Patent Document 2), stomach cancer, colon cancer, rectal cancer (for example, see Non-Patent Documents 3 and 4), non-small cell lung cancer (for example, see Non-Patent Document 5), ovarian cancer (for example, , See Non-Patent Document 6) and the like. Changes in Src activity are associated with changes in the cell cycle (see, for example, Non-Patent Document 7), and changes in regulation of Src activity are also associated with tumorigenesis (for example, Non-Patent Documents 8, 9, 10 and 11). Furthermore, antisense Src expressed in ovarian cancer and rectal cancer cells has been shown to inhibit cancer growth (see, for example, Non-Patent Documents 6 and 12). Therefore, Src inhibitors are expected to suppress cancer cell growth.

  Src is also involved in the control of osteoclastic bone resorption (see, for example, Non-Patent Documents 13, 14, 15 and 16). Src gene knockout mice have been shown to cause bone mineralization (see, for example, Non-Patent Document 13). In addition, it is known that Herbimycin A, an Src inhibitor, inhibits osteoclastic bone resorption in vivo (see, for example, Non-Patent Document 17). Therefore, inhibitors of Src are expected to be useful as preventive or therapeutic agents for bone diseases (eg, osteoporosis, Paget's disease, hypercalcemia, osteoarthritis, etc.).

Src is involved in the control of activation of NMDA receptors in nerve cells (see, for example, Non-Patent Document 18). It is considered that Src inhibitors release the excitotoxicity of glutamate by suppressing the influx of Ca ²⁺ into nerve cells and show a neuroprotective action. Src is also involved in suppression of production of MMP-9 (matrix metalloproteinase 9) (see, for example, Non-Patent Document 19). MMP-9 is produced in response to cerebral ischemia such as stroke and brain injury, and is considered to be one cause of blood-brain barrier breakdown. This breakdown of the blood-brain barrier after cerebral ischemia is thought to result in cerebral edema and acute cerebral infarction. It has also been reported that Src kinase is strongly expressed in neurons after ischemia-reperfusion in a cerebral infarction model. Src is also involved in the migration and adhesion of inflammatory cells, and Src inhibitors are thought to suppress the inhibition of neutrophil adhesion to inflammatory sites and the production of active oxygen from neutrophils (for example, (See Patent Document 20). Src is also involved in the control of MAPK (Mitogen-activated protein kinase) activation. MAPK is activated after cerebral hemorrhage, and its relationship with the occurrence of cerebral vasospasm has been pointed out. Therefore, Src inhibitors are expected to suppress cerebral vasospasm after cerebral hemorrhage (see, for example, Non-Patent Document 21). Thus, since the Src inhibitor has a brain protective action, it is expected to be useful as a preventive or therapeutic agent for Parkinson's disease, epilepsy, cerebral edema, acute cerebral infarction, cerebral vasospasm and the like.

Lck is involved in T cell activation in the immune response. When T cells bind to the antigen presented to the major histocompatibility complex (MHC) on the antigen-presenting cell via the T cell receptor (TCR), the signal is transmitted into the cytoplasm and the TCR / CD3ζ chain The tyrosine residue at the site called immunoreceptor tyrosine-based activation motifs (ITAM) is phosphorylated by Lck. ZAP-70 is recruited to this phosphorylated ITAM, and ZAP-70 is activated when the tyrosine residue of ZAP-70 is phosphorylated by Lck. Activated ZAP-70 further mediates downstream signal transduction, causing intracellular Ca ²⁺ mobilization, production of interleukin 2, proliferation of T cells, and the like (see, for example, Non-Patent Document 22). Therefore, inhibitors of Lck are T cell-related diseases such as autoimmune diseases (eg, psoriasis, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, nephrotic syndrome), graft-versus-host disease, rejection due to organ transplantation It is expected to be useful as a therapeutic agent for suppressing reactions.

Hartz RA et al. Are CRH (Corticotropin Releasing Hormone) receptor ligands, which have the general formula:
Wherein R ^A is a lower alkyl group; R ^B is a lower alkyl group; R ^C is a hydrogen atom or a lower alkyl group; Ar is a 2,4-dichlorophenyl group or 2,4,6-trimethyl. (It is a phenyl group), but imidazo [1,5-a] pyrazine derivatives are disclosed, but it is not described that these compounds have a protein tyrosine kinase inhibitory activity (for example, Non-Patent Document 23). reference).

Hirst GC et al. Are useful as protein tyrosine kinase inhibitors, the general formula:
Wherein R ^D is a phenyl group that may be substituted; R ^E is a cycloalkyl group that may be substituted; R ^F is a hydrogen atom, and the like. a] A pyrazine derivative is disclosed (for example, see Patent Document 1).
Schlessinger J. et al., `` Neuron '', 1992, 9, 383-391 Muthuswamy et al., “Oncogene”, 1995, 11, p.1801-1810 Cartwright CA. et al., "Proc. Natl. Acad. Sci. USA", 1990, 87, p.558-562 Mao et al., "Oncogene", 1997, 15, p.3083-3090 Budde RJA. Et al., “Cancer Biochem. Biophys.”, 1994, 14, 171-175 Wiener JR. Et al., `` Clinical Cancer Research '', 1999, 5, 2164-2170 Chackalaparampil I. et al., `` Cell '', 1988, 52, p.801-810 Bolen JB. Et al., "Proc. Natl. Acad. Sci.", 1985, 82, p.7275-7279 Bolen JB. Et al., "Oncogene res.", 1987, Volume 1, p.149-168 Zheng XM. Et al., `` Nature '', 1992, 359, 336-339 Sabe H. et al., “Mol. Cell Biol.”, 1992, 12, p. 4706-4713 Staley et al., “Cell Growth Diff.”, 1997, 8, p.269 Soriano et al., "Cell", 1991, 64, p.693-702 Boyce et al., “J. Clin. Invest.”, 1992, 90, p.1622-1627 Yoneda et al., "J. Clin. Invest.", 1993, 91, p.2791-2795 Missbach et al., “Bone”, 1999, 24, p.437-449 Rodan GA. Et al., `` Science '', 2000, 289, p. 1508-1514 Lu WY. Et al., "Nat. Neurosci.", 1999, Vol. 2, 331-338 Sato H. et al., “J. Biol. Chem.”, 1993, 31, p. 23460-23468 Mocsai A. et al., "J. Immunol.", 1999, 162, p.1120-1126 Kusaka G. et al., “J. Neurosurg.”, 2003, 99, p.383-390 Chu DH. Et al., "Immunological Reviews", 1998, 165, 167-180 Hartz RA et al., “Bioorg. Med. Chem. Lett.”, 2002, p.291-294 International Publication No. 01/19828 Pamphlet

  The object of the present invention is to provide a novel compound having protein tyrosine kinase inhibitory action, preferably Src family kinase inhibitory action.

  As a result of intensive studies to solve the above problems, the present inventors have found that the imidazo [1,5-a] pyrazine derivative represented by the general formula (I) has an excellent Src family kinase inhibitory action. As a result, the present invention has been completed.

That is, the present invention relates to the general formula (I):
[Where,
R ¹ is a hydrogen atom or a lower alkyl group;
R ² is a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower acyl group;
R ³ and R ⁴ are each independently the following a) to e):
a) a hydrogen atom,
b) a halogen atom,
c) a lower alkyl group,
d) a phenyl group which is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of X ¹ , X ² and X ³ , or e) a heteroaryl group,
Here, X ¹ , X ² and X ³ are each independently the following a) to m):
a) a halogen atom,
b) a lower alkyl group,
c) a halo lower alkyl group,
d) a hydroxy lower alkyl group,
e) a lower alkoxy group,
f) a halo lower alkoxy group,
g) hydroxyl group,
h) -OP (O) (OR 6) 2,
i) a nitro group,
^{j) -A 1 -NR 7 R 8} ,
^k) -A 2 ^-R 9,
l) —O—A ³ —R ¹⁰ , or m) —O—A ⁴ —O—A ⁵ —R ¹¹ ;
R ⁵ represents the following a) to c):
a) a phenyl group which is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of X ⁴ , X ⁵ and X ⁶ ;
b) a heteroaryl group, or c) an aralkyl group,
Here, X ⁴ , X ⁵ and X ⁶ each independently represent a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a hydroxyl group or a cyano group, or X ⁴ , X ⁵ and X 6 If two adjacent of ^6, they are bonded to - _(CH 2) n-is formed, wherein, n represents an integer of 3-5;
R ⁶ is a hydrogen atom, a lower alkyl group or an aralkyl group;
R ⁷ and R ⁸ are each independently the following a) to d):
a) a hydrogen atom,
b) a lower alkyl group,
c) a group consisting of: a lower alkyl group substituted with a group selected from a hydroxyl group, an amino group, a lower alkylamino group, a di-lower alkylamino group and a cyclic amino group, or d) an unsubstituted group or a group consisting of: Represents a phenyl group substituted with 1 to 3 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a hydroxyl group and a cyano group,
Alternatively, R ⁷ and R ⁸ together with the nitrogen atom to which they are attached are unsubstituted or from the group consisting of: a lower alkyl group, a hydroxyl group, a hydroxy lower alkyl group, a lower acyl group, and a lower alkoxycarbonyl group Forming a cyclic amino group substituted with a selected group;
R ⁹ is a formyl group, a carboxy group, a lower alkoxycarbonyl group, a cyano group, or —C (O) NR ⁷ R ⁸ ;
R ¹⁰ is a carboxy group, a lower alkoxycarbonyl group, —C (O) NR ⁷ R ⁸ , —NR ⁷ R ⁸ or a heterocyclyl group;
R ¹¹ is a di-lower alkylamino group or a cyclic amino group;
A ¹ is a bond or a C _1-6 alkylene group;
A ² is a bond, a C _1-6 alkylene group or a C _2-6 alkenylene group;
A ³ is a C _1-6 alkylene group;
A ⁴ and A ⁵ each independently represents a C _2-4 alkylene group], a prodrug thereof, or a pharmaceutically acceptable salt thereof.

  In another aspect, the present invention relates to a pharmaceutical composition containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

  In yet another aspect, the present invention relates to a therapeutic or prophylactic agent for protein tyrosine kinase-related diseases, comprising as an active ingredient the compound described in general formula (I) or a pharmacologically acceptable salt thereof.

  In the compound represented by the general formula (I), the following terms have the following meanings unless otherwise specified.

  The “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

  “Lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl. Group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group and the like. Is an alkyl group having 1 to 4 carbon atoms, more preferably a methyl group or an ethyl group, and most preferably a methyl group.

  The “halo lower alkyl group” means a lower alkyl group substituted with 1 to 3 of the same or different halogen atoms, and examples thereof include a fluoromethyl group, a chloromethyl group, a bromomethyl group, a difluoromethyl group, and trifluoro Examples thereof include a methyl group and a 2,2,2-trifluoroethyl group, and a trifluoromethyl group or a 2,2,2-trifluoroethyl group is preferable.

  “Hydroxy lower alkyl group” means a lower alkyl group substituted with a hydroxyl group, for example, hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxypropyl group, 4-hydroxybutyl group. And 2-hydroxy-2-methylpropyl group.

  The “lower alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec- A butoxy group, a tert-butoxy group, a pentyloxy group, a hexyloxy group, and the like, preferably an alkoxy group having 1 to 4 carbon atoms, more preferably a methoxy group or an ethoxy group, most preferably It is a methoxy group.

  The “halo lower alkoxy group” means a lower alkoxy group substituted with 1 to 3 of the same or different halogen atoms, such as a difluoromethoxy group, a trifluoromethoxy group, 2,2,2-trifluoro. Examples thereof include an ethoxy group and 1,1,2,2,2-pentafluoroethoxy group, and a 2,2,2-trifluoroethoxy group is preferred.

  "Lower acyl group" means a group represented by H-CO- or (lower alkyl) -CO-, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl Group, pivaloyl group and the like.

  The “lower alkoxycarbonyl group” means a group represented by (lower alkoxy) —CO—, and includes, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxy Examples include a carbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group and the like.

  The “lower alkylamino group” means an amino group substituted with a lower alkyl group, and examples thereof include a methylamino group, an ethylamino group, an isopropylamino group, a butylamino group, and a pentylamino group. Is a methylamino group, an ethylamino group or an isopropylamino group.

  The “di-lower alkylamino group” means an amino group that is disubstituted with the same or different lower alkyl groups, such as a dimethylamino group, a diethylamino group, a diisopropylamino group, a dibutylamino group, a dipentylamino group, and the like. Preferably, it is a dimethylamino group, a diethylamino group or a diisopropylamino group.

  “Cyclic amino group” means a 5- to 7-membered cyclic amine which may contain —NH—, —O— or —S— in the ring. For example, 1-pyrrolidyl group, piperidino group, piperazino group , A morpholino group, a thiomorpholino group, and the like, and a 1-pyrrolidyl group, a morpholino group, or a piperazino group is preferable.

  The “heterocyclyl group” means a 4 to 7-membered saturated heterocyclic group containing —NH—, —O— or —S— in the ring, and examples thereof include a tetrahydrofuryl group, a tetrahydrothienyl group, and a tetrahydropyranyl group. Group, pyrrolidin-2-yl group, pyrrolidin-3-yl group, piperidin-2-yl group, piperidin-3-yl group, piperidin-4-yl group, etc., preferably pyrrolidin-2-yl group Pyrrolidin-3-yl group, piperidin-2-yl group, piperidin-3-yl group or piperidin-4-yl group, more preferably pyrrolidin-3-yl group or piperidin-3-yl group And most preferably a piperidin-3-yl group. The heterocyclyl group may be optionally substituted with 1 to 4 lower alkyl groups. Examples of such a substituted heterocyclyl group include an N-methylpyrrolidin-2-yl group and N-methylpyrrolidine-3. -Yl group, N-methylpiperidin-2-yl group, N-methylpiperidin-3-yl group and the like.

A “heteroaryl group” is a 5-6 membered monocyclic containing 1 to 5 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of O, N and S atoms An aromatic heterocycle or an 8-10 membered bicyclic aromatic containing 1 to 4 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of O, N and S atoms Means heterocycle.
Examples of the monocyclic aromatic heterocycle include pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, triazolyl, Examples include pyridyl, pyrazinyl, pyrimidyl and pyridazinyl, and thienyl or pyridyl is preferable. Examples of the bicyclic aromatic heterocycle include indolyl, indazolyl, benzofuranyl, benzothienyl, quinolyl, isoquinolyl, phthalazinyl, benzimidazolyl and the like, and indolyl is preferable. All positional isomers of these heterocycles are contemplated (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.). These aromatic heterocycles are independently selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a formyl group, a di-lower alkylamino lower alkyl group or a cyclic amino lower alkyl group as necessary. May be substituted with ~ 5 groups, and examples of such substituted heteroaryl groups include 2- (N, N-dimethylaminomethyl) thienyl, 2- (N, N-diethylaminomethyl) thienyl, 2- (1-pyrrolidinomethyl) thienyl, 2- (1-piperidinomethyl) thienyl, 2- (4-methylpiperazinomethyl) thienyl, 2- (4-morpholinomethyl) thienyl, 2-methyl-3-pyridyl, 4 -Methyl-3-pyridyl, 6-methoxy-3-pyridyl, 2-chloro-3-pyridyl and the like.

  The “aralkyl group” is unsubstituted or a group consisting of the following: a phenyl group substituted with 1 to 3 groups independently selected from a halogen atom, a lower alkyl group, a lower alkoxy group and a hydroxyl group, or heteroaryl It means a lower alkyl group substituted with a group, and examples thereof include a benzyl group, a phenethyl group, a 3-phenylpropyl group, a 2-methylbenzyl group, and a 2,6-dimethylbenzyl group.

The “C _1-6 alkylene group” means a divalent straight chain saturated hydrocarbon chain having 1 to 6 carbon atoms, and the hydrocarbon chain is optionally substituted with 1 to 3 methyl groups. Also good. Specific examples of the _{C 1-6} alkylene group, _{e.g., -CH 2 -, - CH 2} CH 2 -, - CH (CH 3) -, - CH (CH 3) CH 2 -, - CH 2 CH (CH _{3) -, - C (CH} 3) 2 -, - C (CH 3) 2 CH 2 -, - CH 2 C (CH 3) 2 -, - CH 2 CH 2 CH 2 -, - C (CH 3) ₂ CH ₂ CH ₂ —, —C (CH ₃ ) ₂ CH ₂ CH (CH ₃ ) —, —CH ₂ CH ₂ CH ₂ CH ₂ —, —CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ —, —CH ₂ And a group such as CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ — and the like, preferably a C _1-4 alkylene group, more preferably —CH ₂ —, —CH ₂ CH ₂ —, —CH ₂ C. _{(CH 3) 2 -, -} C (CH 3) 2 CH 2 -, or _-CH 2 CH CH ₂ - is.

The “C _2-4 alkylene group” means a divalent straight chain saturated hydrocarbon chain having 2 to 4 carbon atoms, and the hydrocarbon chain is optionally substituted with 1 to 3 methyl groups. Also good. Specific examples of the C _2-4 alkylene group include, for example, —CH ₂ CH ₂ —, —CH (CH ₃ ) CH ₂ —, —CH ₂ CH (CH ₃ ) —, —C (CH ₃ ) ₂ CH _{2. -, - CH 2 C (CH} 3) 2 -, - CH 2 CH 2 CH 2 -, - C (CH 3) 2 CH 2 CH 2 -, - C (CH 3) 2 CH 2 CH (CH 3) - , —CH ₂ CH ₂ CH ₂ CH ₂ — and the like, and —CH ₂ CH ₂ — is preferred.

The “C _2-6 alkenylene group” means a linear or branched divalent unsaturated hydrocarbon chain having at least one double bond, for example, —CH═CH—, —C (CH ₃ ) ═CH—, —CH═CHCH ₂ —, —CH ₂ CH═CH— and the like can be mentioned, and —CH═CH— is preferred.

  When one or more asymmetric carbon atoms are present in the compound represented by the general formula (I) of the present invention, the present invention is a compound in which each asymmetric carbon atom is R configuration, S configuration compound, And any combination of these compounds. Also included within the scope of the present invention are those racemates, racemic mixtures, single enantiomers and diastereomeric mixtures. When geometric isomerism exists in the compound represented by the general formula (I) of the present invention, the present invention includes any of the geometric isomers. Furthermore, the compound represented by the general formula (I) of the present invention includes solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.

  The compound represented by the general formula (I) of the present invention can exist in the form of a salt. Such salts include addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, Addition salts with organic acids such as p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid And salts with inorganic bases such as sodium salt, potassium salt and calcium salt, and salts with organic bases such as triethylamine, piperidine, morpholine and lysine.

  In the present invention, “prodrug” means a compound that is converted into the above general formula (I) in vivo, and such prodrug is also within the scope of the present invention. Various forms of prodrugs are well known in the art.

For example, when the compound represented by the general formula (I) has a hydroxyl group, as a prodrug, a hydrogen atom of the hydroxyl group and the following group: lower acyl group (for example, acetyl group, propionyl group, butyryl group) , Isobutyryl group, pivaloyl group, etc.); lower alkoxycarbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group, etc.); or formed by substitution with succinoyl group Compounds. Further, when the compound represented by the general formula (I) has an amino group such as —NH or —NH ₂ , as a prodrug, a hydrogen atom of the amino group and the following group: lower acyl group (For example, acetyl group, propionyl group, butyryl group, isobutyryl group, pivaloyl group, etc.); or lower alkoxycarbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group) And the like). These prodrug compounds can be produced from compound (I) by a method known per se.

A preferred embodiment of the compound represented by formula (I) is:
R ¹ is a compound or a pharmaceutically acceptable salt thereof in which R ¹ is a hydrogen atom.

A further preferred embodiment of the compound represented by formula (I) is:
R ¹ is a hydrogen atom,
R ² is a hydrogen atom or a pharmacologically acceptable salt thereof.

Still further preferred embodiments of the compounds represented by general formula (I) are:
R ¹ is a hydrogen atom;
R ² is a hydrogen atom;
A phenyl group in which one of R ³ and R ⁴ is a hydrogen atom and the other is unsubstituted or substituted with ^{1 to 3} groups independently selected from the group consisting of X ¹ , X ² and X ³ Or a heteroaryl group,
In one aspect, R ³ is unsubstituted or substituted with ^{1 to 3} groups independently selected from the group consisting of X ¹ , X ² and X ³ , or a heteroaryl group,
R ⁴ is a hydrogen atom,
In another aspect, R ³ is a hydrogen atom, and R ⁴ is unsubstituted or substituted with ^{1 to 3} groups independently selected from the group consisting of X ¹ , X ² and X ³ , Or a heteroaryl group,
Here, X ¹ , X ² and X ³ are each independently the following a) to m):
a) a halogen atom,
b) a lower alkyl group,
c) a halo lower alkyl group,
d) a hydroxy lower alkyl group,
e) a lower alkoxy group,
f) a halo lower alkoxy group,
g) hydroxyl group,
h) -OP (O) (OR 6) 2,
i) a nitro group,
^{j) -A 1 -NR 7 R 8} ,
^k) -A 2 ^-R 9,
l) —O—A ³ —R ¹⁰ , or m) —O—A ⁴ —O—A ⁵ —R ¹¹ ;
R ⁵ is the following a) to c):
a) a phenyl group which is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of X ⁴ , X ⁵ and X ⁶ ;
b) a heteroaryl group, or c) an aralkyl group,
Here, X ⁴ , X ⁵ and X ⁶ each independently represent a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a hydroxyl group or a cyano group, or X ⁴ , X ⁵ and X 6 If two adjacent of ^6, they are bonded to - _(CH 2) n-is formed, wherein, n is an integer of 3-5;
R ⁶ is a hydrogen atom, a lower alkyl group or an aralkyl group;
R ⁷ and R ⁸ are each independently the following a) to d):
a) a hydrogen atom,
b) a lower alkyl group,
c) a group consisting of: a lower alkyl group substituted with a group selected from a hydroxyl group, an amino group, a lower alkylamino group, a di-lower alkylamino group and a cyclic amino group, or d) an unsubstituted group or a group consisting of: Represents a phenyl group substituted with 1 to 3 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a hydroxyl group and a cyano group,
Alternatively, R ⁷ and R ⁸ together with the nitrogen atom to which they are attached are unsubstituted or from the group consisting of: a lower alkyl group, a hydroxyl group, a hydroxy lower alkyl group, a lower acyl group, and a lower alkoxycarbonyl group Forming a cyclic amino group substituted with a selected group;
R ⁹ is a formyl group, a carboxy group, a lower alkoxycarbonyl group, a cyano group, or —C (O) NR ⁷ R ⁸ ;
R ¹⁰ is a carboxy group, a lower alkoxycarbonyl group, —C (O) NR ⁷ R ⁸ , —NR ⁷ R ⁸ or a heterocyclyl group;
R ¹¹ is a di-lower alkylamino group or a cyclic amino group;
A ¹ is a bond or a C _1-6 alkylene group;
A ² is a bond, a C _1-6 alkylene group or a C _2-6 alkenylene group;
A ³ is a C _1-6 alkylene group;
A ⁴ and A ⁵ are each independently a compound having a C _2-4 alkylene group or a pharmaceutically acceptable salt thereof.

Still further preferred embodiments of the compounds represented by general formula (I) are:
R ¹ is a hydrogen atom;
R ² is a hydrogen atom;
A phenyl group in which one of R ³ and R ⁴ is a hydrogen atom and the other is unsubstituted or substituted with ^{1 to 3} groups independently selected from the group consisting of X ¹ , X ² and X ³ Or a heteroaryl group,
In one aspect, R ³ is a phenyl group which is unsubstituted or substituted with ^{1 to 3} groups independently selected from the group consisting of X ¹ , X ² and X ³ , and R ⁴ is a hydrogen atom Yes,
In another aspect, R ³ is a heteroaryl group, R ⁴ is a hydrogen atom,
In yet another aspect, R ³ is a hydrogen atom and R ⁴ is unsubstituted or substituted with ^{1 to 3} groups independently selected from the group consisting of X ¹ , X ² and X ³ And
In yet another aspect, R ³ is a hydrogen atom, R ⁴ is a heteroaryl group,
Here, X ¹ , X ² and X ³ are each independently the following a) to h):
a) a halogen atom,
b) a lower alkyl group,
c) a lower alkoxy group,
d) a hydroxyl group,
^{e) -A 1 -NR 7 R 8} ,
f) R ⁹ ,
g) —O—A ³ —R ¹⁰ , or h) —O—A ⁴ —O—A ⁵ —R ¹¹ ;
R ⁵ is unsubstituted or a group consisting of the following: a phenyl group substituted with 1 to 3 groups selected from a halogen atom, a lower alkyl group, a halo lower alkyl group and a lower alkoxy group;
R ⁷ and R ⁸ are each independently the following a) to c):
a) a hydrogen atom,
b) a lower alkyl group, or c) a group consisting of: a lower alkyl group substituted with a group selected from an amino group, a lower alkylamino group, a di-lower alkylamino group and a cyclic amino group,
Or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a cyclic amino group that is unsubstituted or substituted with a lower alkyl group;
R ⁹ is —C (O) NR ⁷ R ⁸ ;
R ¹⁰ is —NR ⁷ R ⁸ or a heterocyclyl group;
R ¹¹ is a di-lower alkylamino group or a cyclic amino group;
A ¹ is a bond or a C _1-6 alkylene group;
A ³ is a C _1-6 alkylene group;
A ⁴ and A ⁵ are each independently a compound having a C _2-4 alkylene group or a pharmaceutically acceptable salt thereof.

A particularly preferred embodiment of the present invention is represented by the general formula (II):
[Where,
R ⁵ is unsubstituted or a phenyl group substituted with 1 to 3 groups selected from the group consisting of: a halogen atom, a lower alkyl group, a halo lower alkyl group and a lower alkoxy group;
X ¹⁰ is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group;
X ²⁰ represents the following a) to d):
^{a) -A 1 -NR 7 R 8} ,
b) -C (O) NR < ⁷ > R < ⁸ >,
c) —O—A ³ —R ¹⁰ , or d) —O—A ⁴ —O—A ⁵ —R ¹¹ ;
R ⁷ and R ⁸ are each independently the following a) to c):
a) a hydrogen atom,
b) a lower alkyl group, or c) a group consisting of: a lower alkyl group substituted with a group selected from an amino group, a lower alkylamino group, a di-lower alkylamino group and a cyclic amino group,
Or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a cyclic amino group that is unsubstituted or substituted with a lower alkyl group;
R ¹⁰ is —NR ⁷ R ⁸ or a heterocyclyl group;
R ¹¹ is a di-lower alkylamino group or a cyclic amino group;
A ¹ is a bond or a C _1-6 alkylene group, more preferably a C _1-6 alkylene group, still more preferably a C _1-4 alkylene group, and most preferably —CH ₂ —;
A ³ is a C _1-6 alkylene group, more preferably a C _1-4 alkylene group, still more preferably —CH ₂ —, —CH ₂ CH ₂ — or —C (CH ₃ ) ₂ CH _2. -Is;
A ⁴ and A ⁵ are each independently a C _2-4 alkylene group, and most preferably —CH ₂ CH ₂ —) or a pharmacologically acceptable salt thereof. .

Another particularly preferred embodiment of the invention is represented by the general formula (III):
[Where,
R ⁵ is unsubstituted or a phenyl group substituted with 1 to 3 groups selected from the group consisting of: a halogen atom, a lower alkyl group, a halo lower alkyl group and a lower alkoxy group;
X ¹⁰ is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group;
X ²⁰ represents the following a) to d):
^{a) -A 1 -NR 7 R 8} ,
b) -C (O) NR < ⁷ > R < ⁸ >,
c) —O—A ³ —R ¹⁰ , or d) —O—A ⁴ —O—A ⁵ —R ¹¹ ;
R ⁷ and R ⁸ are each independently the following a) to c):
a) a hydrogen atom,
b) a lower alkyl group, or c) a group consisting of: a lower alkyl group substituted with a group selected from an amino group, a lower alkylamino group, a di-lower alkylamino group and a cyclic amino group,
Or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a cyclic amino group that is unsubstituted or substituted with a lower alkyl group;
R ¹⁰ is —NR ⁷ R ⁸ or a heterocyclyl group;
R ¹¹ is a di-lower alkylamino group or a cyclic amino group;
A ¹ is a bond or a C _1-6 alkylene group, more preferably a C _1-6 alkylene group, still more preferably a C _1-4 alkylene group, and most preferably —CH ₂ —;
A ³ is a C _1-6 alkylene group, more preferably a C _1-4 alkylene group, still more preferably —CH ₂ —, —CH ₂ CH ₂ — or —C (CH ₃ ) ₂ CH _2. -Is;
A ⁴ and A ⁵ are each independently a C _2-4 alkylene group, and most preferably —CH ₂ CH ₂ —) or a pharmacologically acceptable salt thereof. .

Specific examples of preferred embodiments of the invention are the following compounds or pharmacologically acceptable salts thereof:
2,6-dimethylphenyl- {5- [4- (2-morpholin-4-ylethylamino) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine (Compound 7-1);
{5- [4- (2-dimethylaminoethoxy) phenyl] imidazo [1,5-a] pyrazin-8-yl} -2,6-dimethylphenylamine (Compound 8-2);
2,6-dimethylphenyl- {5- [4- (2-pyrrolidin-1-ylethoxy) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine (Compound 8-6);
2,6-dimethylphenyl- {5- [4- (1-methylpiperidin-3-ylmethoxy) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine (Compound 8-10);
2,6-dimethylphenyl- {5- [3- (1-methylpiperidin-3-ylmethoxy) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine (Compound 8-12);
N- (2-dimethylaminoethyl) -4- [8- (2,6-dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] benzamide (Compound 10-11);
2,6-dimethylphenyl- {5- [4- (4-methylpiperazin-1-ylmethyl) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine (Compound 12-1);
[5- (4-dimethylaminomethylphenyl) imidazo [1,5-a] pyrazin-8-yl)]-2,6-dimethylphenylamine (Compound 12-2);
2,6-Dimethylphenyl- {5- [5- (4-methylpiperazin-1-ylmethyl) thiophen-2-yl] imidazo [1,5-a] pyrazin-8-yl} amine dihydrochloride (compound 12 -16);
2,6-Dimethylphenyl- [5- (5-pyrrolidin-1-ylmethylthiophene-2
-Yl) imidazo [1,5-a] pyrazin-8-yl] amine hydrochloride (compound 12-17);
2-chloro-6-methylphenyl- [6- (2-methoxyphenyl) imidazo [1,5-a] pyrazin-8-yl] amine (compound 16-11); or 4- [8- (2-chloro -6-Methylphenylamino) imidazo [1,5-a] pyrazin-6-yl] -N- (2-dimethylaminoethyl) benzamide (Compound 19-4).

  The compound represented by the general formula (I) of the present invention can be produced by the methods shown in Schemes 1 to 4.

Wherein R ³ and R ⁵ are as defined above, P ¹ is a protecting group such as p-methoxybenzyl group, CH ₂ CH ₂ CH (OCH ₃ ) ₂ , and Tos is a p-toluenesulfonyl group. Represent)

Step 1-1
The 1H-pyrazin-2-one derivative (XII) is obtained by condensing the 2-oxoaldehyde derivative (X) and glycinamide (XI) in the presence of a base in an appropriate solvent. Examples of the solvent used in the reaction include methanol, ethanol, water, and tetrahydrofuran. Examples of the base include sodium hydroxide and potassium hydroxide. The reaction temperature is usually from −40 ° C. to room temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw materials and solvents used and the reaction temperature.

Step 1-2
1H-pyrazin-2-one derivative (XII) is present in the presence of a base (eg, sodium hydride) in an inert solvent (eg, tetrahydrofuran, N, N-dimethylformamide, 1-methyl-2-pyrrolidone, etc.). By using a suitable protecting reagent below, it can be converted to a compound (XIII) in which the nitrogen atom is protected. Examples of such a protecting reagent include 4-methoxybenzyl chloride, 3-bromopropionaldehyde dimethyl acetal, and the like.

Step 1-3
Compound (XIII) and p-toluenesulfonylmethyl isocyanide (XIV) are condensed in the presence of a base in an inert solvent to obtain an imidazo [1,5-a] pyrazinone derivative (XV). Examples of the solvent used in the reaction include tetrahydrofuran, N, N-dimethylformamide, 1-methyl-2-pyrrolidone and the like. Examples of the base include sodium hydride, n-butyl lithium, lithium, sodium and cesium carbonate. The reaction temperature is usually from −10 ° C. to 100 ° C., and the reaction time is usually from 30 minutes to 24 hours, although it varies depending on the raw materials and solvents used and the reaction temperature.

Step 1-4
The imidazo [1,5-a] pyrazinone derivative (XV) can be converted to compound (XVI) by deprotection using an appropriate deprotection reagent. For example, when the protecting group P ¹ is a p-methoxybenzyl group, an acid such as trifluoroacetic acid or trifluoromethanesulfonic acid is used as a deprotecting reagent in an inert solvent (eg, anisole). When the protecting group P ¹ is a 3,3-dimethoxypropyl group, an acid (eg, oxalic acid, hydrochloric acid, etc.) is used in an inert solvent (tetrahydrofuran, acetone, water, etc.) to form a 3,3-dimethylacetal group. Is hydrolyzed to formyl group, and then a base (for example, piperazine, piperidine, etc.) is used.

Step 1-5
Compound (XVI) can be converted to chloroimidate derivative (XVII) by halogenation using a halogenating reagent in a solvent-free or inert solvent. Examples of the solvent used in the reaction include toluene, methylene chloride, benzene and the like. As the halogenating reagent, for example, phosphorus oxychloride, thionyl chloride, phosphorus pentachloride and the like are used. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw materials and solvents used and the reaction temperature.

Step 1-6
By condensing the chloroimidate derivative (XVII) and the amine derivative (XVIII) in an appropriate solvent in the presence or absence of a base, an imidazo [1,5-a] pyrazine derivative (Ia) is obtained. It is done. Examples of the solvent used in the reaction include tetrahydrofuran, 1-methyl-2-pyrrolidone, and the like. Examples of the base include sodium, potassium, sodium bis (trimethylsilyl) amide, cesium carbonate, triethylamine and the like. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw materials and solvents used and the reaction temperature.

(Wherein R ³ , R ⁵ , P ¹ and Tos are as defined above, and n-Bu represents an n-butyl group)

Step 2-1
The 5-bromo-1H-pyrazin-2-one derivative (XIX) is prepared from a base (eg, sodium hydride) in an inert solvent (eg, tetrahydrofuran, N, N-dimethylformamide, 1-methyl-2-pyrrolidone, etc.). Etc.) can be converted to compound (XX) in which the nitrogen atom is protected by using a suitable protecting reagent. Examples of such a protecting reagent include 4-methoxybenzyl chloride, 3-bromopropionaldehyde dimethyl acetal, and the like.

Step 2-2
The compound (XX) and p-toluenesulfonylmethyl isocyanide (XIV) are condensed in the presence of a base in an inert solvent to obtain an imidazo [1,5-a] pyrazinone derivative (XXI). Examples of the solvent used in the reaction include tetrahydrofuran, N, N-dimethylformamide, 1-methyl-2-pyrrolidone and the like. Examples of the base include sodium hydride, n-butyllithium, lithium, sodium, cesium carbonate and the like. The reaction temperature is usually from −10 ° C. to 100 ° C., and the reaction time is usually from 30 minutes to 3 hours, although it varies depending on the raw material and solvent used and the reaction temperature.

Step 2-3
The imidazo [1,5-a] pyrazinone derivative (XXI) can be converted to compound (XXII) by deprotection using an appropriate deprotection reagent. For example, when the protecting group P ¹ is a p-methoxybenzyl group, an acid such as trifluoroacetic acid or trifluoromethanesulfonic acid is used as a deprotecting reagent in an inert solvent (eg, anisole). When the protecting group P ¹ is a 3,3-dimethoxypropyl group, an acid (eg, oxalic acid, hydrochloric acid, etc.) is used in an inert solvent (tetrahydrofuran, acetone, water, etc.) to form a 3,3-dimethylacetal group. Is hydrolyzed to formyl group, and then a base (for example, piperazine, piperidine, etc.) is used.

Step 2-4
Compound (XXII) can be converted to chloroimidate derivative (XXIII) by halogenation using a halogenating reagent in a solvent-free or inert solvent. Examples of the solvent used in the reaction include toluene, methylene chloride, benzene and the like. As the halogenating reagent, for example, phosphorus oxychloride, thionyl chloride, phosphorus pentachloride and the like are used. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw materials and solvents used and the reaction temperature.

Step 2-5
The chloroimidate derivative (XXIII) and the amine derivative (XVIII) are condensed in an appropriate solvent in the presence or absence of a base to give a 5-bromoimidazo [1,5-a] pyrazine derivative (Ib ) Is obtained. Examples of the solvent used in the reaction include tetrahydrofuran. Examples of the base include sodium, potassium, sodium bis (trimethylsilyl) amide, cesium carbonate, triethylamine and the like. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw materials and solvents used and the reaction temperature.

Step 2-6
The 5-bromoimidazo [1,5-a] pyrazine derivative (Ib) is condensed with the boronic acid derivative (XXIV) in the presence of a palladium catalyst and a base in an inert solvent to give the imidazo [1,5-a It can be converted to a pyrazine derivative (Ia). Examples of the solvent used in the reaction include tetrahydrofuran, toluene, N, N-dimethylformamide, water, and the like. Examples of the base include potassium acetate, potassium carbonate, cesium carbonate, triethylamine and the like. Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium (0), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex, and the like. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw materials and solvents used and the reaction temperature. In addition, imidazo [1,5-a] pyrazine derivative (Ia) is obtained by similarly combining 5-bromoimidazo [1,5-a] pyrazine derivative (Ib) and tin reagent (XXV) in the presence of a palladium catalyst. It can also be obtained by condensation.

(Wherein R ¹ , R ³ , R ⁴ and R ⁵ are as defined above, R ²⁰ is a lower alkyl group, Y is a chlorine atom or a bromine atom, and Bn represents a benzyl group)

Step 3-1
1-Benzyl-1H-imidazole-4-carboxamide (XXVII) is obtained by condensing 1-benzyl-1H-imidazole-4-carboxylic acid ester (XXVI) and ammonia in the presence of ammonium chloride. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 48 hours, although it varies depending on the raw material used and the reaction temperature.

Step 3-2
Imidazo [1,5-a] pyrazinium salt derivative (XXIX) is obtained by condensing 1-benzyl-1H-imidazole-4-carboxamide (XXVII) and 2-haloketone derivative (XXVIII) in an inert solvent. . Examples of the solvent used in the reaction include tetrahydrofuran, N, N-dimethylformamide, 1-methyl-2-pyrrolidone, acetonitrile, and the like. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 48 hours, although it varies depending on the raw material and solvent used and the reaction temperature.

Step 3-3
The 7H-imidazo [1,5-a] pyrazin-8-one derivative (XXX) is obtained by reacting the imidazo [1,5-a] pyrazinium salt derivative (XXIX) and imidazole without solvent. The reaction temperature is usually from 100 ° C. to 200 ° C., and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material used.

Step 3-4
The 7H-imidazo [1,5-a] pyrazin-8-one derivative (XXX) is converted to the chloroimidate derivative (XXXI) by halogenation using a halogenating reagent in a solvent-free or inert solvent. can do. Examples of the solvent used in the reaction include toluene, methylene chloride, benzene and the like. As the halogenating reagent, for example, phosphorus oxychloride, thionyl chloride, phosphorus pentachloride and the like are used. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw materials and solvents used and the reaction temperature.

Step 3-5
The imidazo [1,5-a] pyrazine derivative (Ic) is obtained by condensing the chloroimidate derivative (XXXI) and the amine derivative (XVIII) in an inert solvent in the presence or absence of a base. . Examples of the solvent used in the reaction include tetrahydrofuran, N, N-dimethylformamide, 1-methyl-2-pyrrolidone, acetonitrile, and the like. Examples of the base include sodium, potassium, sodium bis (trimethylsilyl) amide, cesium carbonate, triethylamine and the like. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw materials and solvents used and the reaction temperature.

(Wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ²⁰ are as defined above, R ²¹ is a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms, L ¹ is a bromine atom, This represents a leaving group such as iodine atom, methanesulfonyloxy group, p-toluenesulfonyloxy group, etc., and Boc represents tert-butoxycarbonyl group)

Step 4-1
The imidazo [1,5-a] pyrazine derivative (Ic) can be converted to a compound (XXXII) by reacting with di-tert-butyl carbonate in an inert solvent in the presence of a base. Examples of the solvent used in this reaction include tetrahydrofuran, 1-methyl-2-pyrrolidone, and the like. Examples of the base include 4-dimethylaminopyridine and sodium bis (trimethylsilyl) amide. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw materials and solvents used and the reaction temperature.

Step 4-2
Compound (XXXII) can be converted to Compound (XXXIII) by condensation with N, N-dimethylformamide in the presence of a base in an inert solvent. Examples of the solvent used in this reaction include tetrahydrofuran and the like. Examples of the base include lithium diisopropylamide and lithium bis (trimethylsilyl) amide. The reaction temperature is usually from −78 ° C. to room temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw materials and solvents used and the reaction temperature.

Step 4-3
Compound (XXXIII) is deprotected with an acid in an appropriate solvent (eg, methylene chloride, ethyl acetate, etc.) to give 3-formylimidazo [1,5-a] pyrazine derivative (Id) . Examples of the acid include trifluoroacetic acid and hydrochloric acid. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material and solvent used and the reaction temperature.

Step 4-4 and Step 4-5
The 3-hydroxyalkylimidazo [1,5-a] pyrazine derivative (XXXV) is obtained by condensing the compound (XXXII) and the aldehyde derivative (XXXIV) in the same manner as in Step 4-2. Subsequently, the 3-hydroxyalkylimidazo [1,5-a] pyrazine derivative (XXXV) is deprotected in the same manner as in Step 4-3 to give a 3-hydroxyalkylimidazo [1,5-a] pyrazine derivative. (Ie).

Step 4-6
The 3-hydroxyalkylimidazo [1,5-a] pyrazine derivative (XXXV) is oxidized with an appropriate oxidizing agent in an inert solvent, followed by deprotection in the same manner as in Step 4-3. It can be converted to a 3-acylimidazo [1,5-a] pyrazine derivative (If). Examples of the solvent used in the oxidation reaction include methylene chloride, N, N-dimethylformamide, and the like. Examples of the oxidizing agent include pyridinium dichromate and manganese dioxide. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material and solvent used and the reaction temperature.

Step 4-7
Compound (XXXII) and alkylating agent (XXXVI) are condensed in the same manner as in Step 4-2, followed by deprotection in the same manner as in Step 4-3 to give 3-alkylimidazo [1,5- a] can be converted to a pyrazine derivative (Ig).

  The schemes shown above are several examples of methods for preparing the compounds of the present invention or their intermediates, and various modifications of these schemes are possible as will be readily understood by those skilled in the art. It is.

  The compound represented by the general formula (I) of the present invention and the intermediate used for producing the compound are isolation / purification means well known to those skilled in the art, if necessary. Isolation and purification can be performed by performing operations such as solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography and the like.

Since the compound of the present invention thus produced has an inhibitory action on Src family kinases, particularly Src and / or Lck kinases, it is useful as a prophylactic or therapeutic agent for diseases caused by abnormal Src family kinase activity.
For example, since the compound of the present invention has an excellent Src kinase inhibitory action, it is useful for suppressing the growth of cancer cells related to the enhancement of Src activity, particularly breast cancer, stomach cancer, colon cancer, rectal cancer, non-small cell cancer, It is useful as a remedy for ovarian cancer.

  Since the compound of the present invention has an excellent Src inhibitory action and shows an osteoclast resorption inhibitory action, it prevents or treats bone diseases such as osteoporosis, Paget's disease, hypercalcemia, osteoarthritis, etc. Useful as a medicine. In addition, the compound of the present invention can be used in combination with a therapeutic agent for bone diseases other than an Src family kinase inhibitor, if necessary. Examples of such bone disease therapeutic agents include bisphosphonates (eg, etidolone disodium, zoledronic acid hydrate, tiludronate disodium, alendronate sodium hydrate, clodronate sodium hydrate, risedronate sodium Active vitamin D agents (eg, calcitriol, cecalciferol, falecalcitriol, alphacalcidol, etc.); progesterone agonists (eg, trimegestone); estrogen agonists (eg, estradiol, guestden, etc.) Androgen antagonists (for example, oseterone acetate); vitamin K agents (for example, menatetrenin); ipriflavone, elcatonin, calcitonin, and the like.

  Since the compound of the present invention has an excellent Src inhibitory action and a brain protective action, it is useful as a preventive or therapeutic agent for Parkinson's disease, epilepsy, cerebral edema, acute cerebral infarction, cerebral vasospasm and the like. In addition, the compound of the present invention can be used in combination with a brain protective agent other than an Src family kinase inhibitor, if necessary. Examples of such cerebral protective drugs include antiparkinsonian drugs, antiepileptic drugs, therapeutic drugs for acute cerebral infarction, and therapeutic drugs for cerebral vasospasm. Antiparkinsonian agents that can be used in combination with the compounds of the present invention include, for example, levodopa, droxidopa, melevodopa; dopamine D2 receptor agonists (eg cabergoline, bromocriptine mesylate, terguride, talipexol hydrochloride, ropinirole hydrochloride, pergolide mesylate, hydrochloric acid Pramipexole, etc.); COMT (catechol O-methyl transferase) inhibitors (eg, tolcapone, entacapone, etc.); NMDA antagonists (eg, budipine); monoamine oxidase B inhibitors (eg, selegiline hydrochloride, etc.) . Antiepileptics that can be used in combination with the compounds of the present invention include, for example, benzodiazepine agonists (eg, clobazam, clonazepam, nitrazepam, etc.); GABA agonists (eg, gabapentin, progabide, topiramate, etc.); sodium channel antagonists (eg, eg, Phenytoin, phosphenytoin sodium, oxcarbazepine, carbamazepine, etc.); phenobarbital, primidone, sodium valproate, zonisamide, vigabatrin, lamotrigine, felbamate, tyagabine hydrochloride and the like. Examples of therapeutic agents for acute cerebral infarction that can be used in combination with the compound of the present invention include thrombolytic agents (for example, t-PA (tissue plasminogen activator), urokinase, etc.); thrombin inhibitors (for example, argatroban, etc.); TXA2 Synthetic enzyme inhibitors (eg, ozagrel sodium, etc.); radical scavengers (eg, ebselen, edaravone, nicarabene, etc.); 5-HT1A agonists (eg, SUN-N4057, BAYx 3702, etc.); AMPA antagonists (for example, S-1746 and the like); dilazep hydrochloride, citicoline and the like. Examples of therapeutic agents for cerebral vasospasm that can be used in combination with the compound of the present invention include TXA2 synthase inhibitors (for example, ozagrel sodium); Rho kinase inhibitors (for example, fasudil).

  Since the compound of the present invention has an excellent Lck inhibitory action, diseases involving T cells such as autoimmune diseases (psoriasis, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, nephrotic syndrome, etc.), grafts It is useful as a prophylactic or therapeutic agent for host disease, suppression of rejection due to organ transplantation, and the like. Moreover, the compound of this invention can be used in combination with the therapeutic agent of T cell related diseases other than a Src family kinase inhibitor as needed. Examples of therapeutic agents for such T cell-related diseases include immunosuppressants (eg, cyclosporin A, tacrolimus hydrate, rapamycin, azathioprine, methotrexate, etc.); COX-2 inhibitors (eg, celecoxib, rofecoxib, valdecoxib Steroids (eg, prednisone, dexamethasone, etc.); non-steroidal anti-inflammatory agents (eg, indomethacin, ketoprofen, ibuprofen, etc.); anti-CD-3 antibodies (muromonab), anti-CD-4 antibodies (cederizumab) ), Anti-CD45RB antibody, anti-ICAM-3, anti-IL-2 receptor antibody, anti-TNF-α antibody, and the like.

When the pharmaceutical composition containing the compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient is used for actual treatment, it has various dosage forms depending on the usage. Is used. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches and the like, oral or parenteral. Administered.
These pharmaceutical compositions are prepared according to pharmacologically known methods according to the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives. It can be prepared by mixing or diluting / dissolving appropriately with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents.

  When the pharmaceutical composition of the present invention is used for actual treatment, the dosage of the compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof as the active ingredient is determined by the patient's age, sex, It is appropriately determined depending on body weight, disease and degree of treatment, etc., but in the range of about 0.01 mg to about 1000 mg per day for oral administration, and about 0.001 mg to about 100 mg per day for parenteral administration In this range, it can be appropriately administered once or several times.

  The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof, an agent for bone diseases other than an Src family kinase inhibitor, an antiparkinsonian agent, an antiepileptic agent, a therapeutic agent for brain edema A pharmaceutical comprising a combination of at least one selected from a therapeutic agent for acute cerebral infarction, a therapeutic agent for cerebral vasospasm and a therapeutic agent for T cell-related diseases, wherein these active ingredients are pharmacologically acceptable separately or simultaneously. Mixed with excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers, etc. It can be administered orally or parenterally as a pharmaceutical composition. At this time, when the active ingredients are formulated separately, those separately formulated can be administered by mixing with a diluent at the time of use, but those separately formulated can be separately and simultaneously, Alternatively, it may be administered to the same subject with a time difference.

  The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof, an agent for bone diseases other than an Src family kinase inhibitor, an antiparkinsonian agent, an antiepileptic agent, a therapeutic agent for brain edema In a medicament comprising a combination of at least one selected from a therapeutic agent for acute cerebral infarction, a therapeutic agent for cerebral vasospasm and a therapeutic agent for T cell-related diseases, the compounding ratio of the drug is determined by the age, sex, and weight of the patient, It can be appropriately selected depending on symptoms, administration time, dosage form, administration method, drug combination, and the like.

  The compound of the present invention has an excellent protein tyrosine kinase inhibitory action. Furthermore, preferred compounds of the present invention have a selective inhibitory action on Src family kinases, especially Src and / or Lck. Therefore, the compound of the present invention is useful as a therapeutic or prophylactic agent for diseases caused by abnormal protein tyrosine kinases, particularly cancer, bone diseases (eg, osteoporosis, Paget's disease, hypercalcemia, deformability). Arthritis, etc.), Parkinson's disease, epilepsy, cerebral edema, acute cerebral infarction, cerebral vasospasm, diseases involving T cells (eg, psoriasis, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, nephrotic syndrome, graft) It is suitable as a therapeutic or prophylactic agent for host disease, rejection due to organ transplantation, etc.

  The contents of the present invention will be described in more detail with reference to the following reference examples, examples and test examples, but the present invention is not limited to these contents.

Reference example 1
5-Phenyl-1H-pyrazin-2-one (Compound 1-1)
To a suspension of glycinamide hydrochloride (2.7 g) in methanol (22.5 mL) and water (5.5 mL) was added 12.5 mol / L sodium hydroxide aqueous solution (2.9 mL) at −30 ° C., and sodium hydroxide was further added. A solution of (977 mg) in methanol (11 mL) was added. To the reaction mixture, a solution of phenylglyoxal monohydrate (4.5 g) in methanol (20 mL) was added dropwise at −20 ° C., and the mixture was stirred for 2 hours under the same conditions. After raising the temperature to room temperature, the mixture was further stirred for 1 hour. The reaction mixture was ice-cooled, adjusted to weak acidity with acetic acid, and the precipitate was collected by filtration to give the title compound (3.2 g).
Compound 1-2 to compound 1-6 were synthesized in the same manner as in Reference Example 1 using the corresponding 2-oxoaldehyde derivative instead of phenylglyoxal monohydrate. These are shown in Table 1.

Reference example 2
1- (4-Methoxybenzyl) -5-phenyl-1H-pyrazin-2-one (Compound 2-1)
A suspension of compound 1-1 (2.6 g) in N, N-dimethylformamide (8.0 mL) and tetrahydrofuran (8.0 mL) was added to sodium hydride (60%, 703 mg) in N, N-dimethylformamide (8.0 mL). To the suspension was added at 0 ° C. under an argon atmosphere. After stirring for 30 minutes, 4-methoxybenzyl chloride (2.3 mL) and tetra-n-butylammonium iodide (564 mg) were added. After removing the ice bath, the reaction mixture was stirred at room temperature for 2 hours, and further stirred at 70 ° C. for 1 hour. After ice cooling, a saturated aqueous ammonium chloride solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained crude product was purified by silica gel flash column chromatography (elution solvent: ethyl acetate / hexane = 1/2 to 2/1) to obtain the title compound (2.8 g).
Compound 2-2 to compound 2-6 were synthesized in the same manner as in Reference Example 2 using compound 1-2 to compound 1-6 instead of compound 1-1. These are shown in Table 2.

Reference example 3
1- (3,3-Dimethoxypropyl) -5- (4-methoxyphenyl) -1H-pyrazin-2-one (Compound 2-7)
A suspension of compound 1-2 (102 mg) in N, N-dimethylformamide (250 μL) and tetrahydrofuran (250 μL) was added to a suspension of sodium hydride (55%, 26 mg) in tetrahydrofuran (250 μL) under an argon atmosphere. Added at ° C. After stirring for 30 minutes, 3-bromopropionaldehyde dimethyl acetal (75 μL) and tetra-n-butylammonium iodide (19 mg) were added. After removing the ice bath, the reaction mixture was stirred at room temperature for 19 hours. Further, 3-bromopropionaldehyde dimethyl acetal (57 μL) was added, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting crude product was purified by silica gel flash column chromatography (elution solvent: ethyl acetate / hexane = 2/1) to obtain the title compound (66 mg). This is shown in Table 2.

Reference example 4
7- (4-Methoxybenzyl) -5-phenyl-7H-imidazo [1,5-a] pyrazin-8-one (Compound 3-1)
A solution of compound 2-1 (2.8 g) and p-toluenesulfonylmethyl isocyanide (2.0 g) in tetrahydrofuran (6.0 mL) was suspended in sodium hydride (60%, 830 mg) in N, N-dimethylformamide (10 mL). Was added at 0 ° C. under an argon atmosphere. After stirring for 30 minutes under the same conditions, the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was poured into ice water, and the precipitate was collected by filtration to give the title compound (3.0 g).
Compound 3-2 to compound 3-6 were synthesized in the same manner as in Reference Example 4 using compound 2-2 to compound 2-6 instead of compound 2-1. These are shown in Table 3.

Reference Example 5
7- (3,3-Dimethoxypropyl) -5- (4-methoxyphenyl) -7H-imidazo [1,5-a] pyrazin-8-one (Compound 3-7)
A solution of compound 2-7 (64 mg) and p-toluenesulfonylmethyl isocyanide (54 mg) in tetrahydrofuran (420 μL) was added to a suspension of sodium hydride (55%, 25 mg) in tetrahydrofuran (420 mL) at 0 ° C. under an argon atmosphere. added. After stirring for 30 minutes under the same conditions, the mixture was stirred for 1 hour at room temperature. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography (developing solvent: ethyl acetate) to obtain the title compound (45 mg). This is shown in Table 3.

Reference Example 6
5-Phenyl-7H-imidazo [1,5-a] pyrazin-8-one (Compound 4-1)
A mixture of Compound 3-1 (3.0 g), anisole (17.7 mL), trifluoromethanesulfonic acid (41.8 mL) and trifluoroacetic acid (9.6 mL) was stirred at room temperature for 30 minutes, and further stirred at 40 ° C. for 6 hours. . The reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous sodium hydrogen carbonate, and the precipitate was collected by filtration to give a crude product. A suspension of this crude product in ethyl acetate (50 mL) was stirred under reflux for 2 hours. The insoluble material was collected by filtration to give the title compound (1.2 g).
Compound 4-2 to compound 4-6 were synthesized in the same manner as in Reference Example 6 using compound 3-2 to compound 3-6 instead of compound 3-1. These are shown in Table 4.

Reference Example 7
5- (4-Methoxyphenyl) -7H-imidazo [1,5-a] pyrazin-8-one (Compound 4-2)
Oxalic acid dihydrate was added to a solution of compound 3-7 (44 mg) in acetone (3.3 mL) -water (3.3 mL), and the mixture was stirred at 75 ° C. for 2 hours. After cooling to room temperature, piperazine (67 mg) was added to the reaction mixture, and the mixture was stirred at 75 ° C. for 30 min. After cooling at room temperature, acetone was added to the reaction mixture, the insoluble material was removed by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (35 mg).

Example 1
3-methoxyphenyl- (5-phenylimidazo [1,5-a] pyrazin-8-yl) amine (Compound 5-1)
A suspension of compound 4-1 (150 mg) in phosphorus oxychloride (1.35 mL) was stirred under reflux for 1.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and further azeotropically distilled with toluene to obtain a crude product of 8-chloro-5-phenylimidazo [1,5-a] pyrazine.
A solution of 8-chloro-5-phenylimidazo [1,5-a] pyrazine and 3-methoxyaniline (44 mg) in tetrahydrofuran (0.4 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel thin layer chromatography (developing solvent: ethyl acetate) to obtain the title compound (4.0 mg).
Compound 5-2 to compound 5-41 were synthesized in the same manner as in Example 1, using the corresponding amine derivative instead of 3-methoxyaniline, and using compound 4-1 to compound 4-4. These are shown in Table 5.

Example 2
(2,6-Dimethylphenyl)-[5- (4-methoxyphenyl) imidazo [1,5-a] pyrazin-8-yl] amine (Compound 6-1)
A suspension of compound 4-2 (987 mg) in phosphorus oxychloride (9.0 mL) was stirred under reflux for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and further azeotropically distilled with toluene to give a crude product of 8-chloro-5- (4-methoxyphenyl) imidazo [1,5-a] pyrazine. Obtained.
To a solution of 8-chloro-5- (4-methoxyphenyl) imidazo [1,5-a] pyrazine and 2,6-dimethylaniline (600 μL) in tetrahydrofuran (30 mL) was added sodium bis (trimethylsilyl) amide (10 mL) at room temperature. The mixture was added under stirring and stirred for 1 hour under reflux. After cooling to room temperature, 2,6-dimethylaniline (900 μL) and 1 mol / L sodium bis (trimethylsilyl) amide (15 mL) were added to the reaction mixture and stirred under reflux for 3 hours. Acetic acid (25 mL) was added at room temperature, and the reaction mixture was concentrated under reduced pressure. To this residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate and hexane were added to the residue, and the insoluble material was collected by filtration to obtain the title compound (839 mg).
Compound 6-2 to compound 6-5 were synthesized in the same manner as in Example 2 except that compound 4-3 to compound 4-6 were used instead of compound 4-2. These are shown in Table 6.
Further, Compound 6-8 was synthesized using 2-chloro-6-methylaniline instead of 2,6-dimethylaniline. This is shown in Table 6.

Example 3
(2,6-Dimethylphenyl)-[5- (4-hydroxyphenyl) imidazo [1,5-a] pyrazin-8-yl] amine (Compound 6-6)
Boron tribromide (2.0 mL) was added to a suspension of compound 6-1 (1.78 g) in methylene chloride (20 mL) at −78 ° C. and stirred overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and 10% brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 mL), nitrilotriethanol (7.7 g) was added, and the mixture was stirred overnight under reflux. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and 10% brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in acetonitrile, and the insoluble material was collected by filtration to obtain the title compound (1.39 g).
Compound 6-7 and Compound 6-9 were synthesized in the same manner as Example 3 using Compound 6-2 or Compound 6-8 instead of Compound 6-1. This is shown in Table 6.

Example 4
2,6-Dimethylphenyl- {5- [4- (2-morpholin-4-ylethylamino) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine (Compound 7-1)
Compound 6-3 (30 mg), 4- (2-aminoethyl) morpholine (12 mg), tris (dibenzylideneacetone) dipalladium (0) (17.5 mg), sodium tert-butoxide (10 mg) and (R)-( A toluene suspension of (+)-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP) (3.3 mg) was stirred at 80 ° C. overnight under an argon atmosphere. After cooling to room temperature, diethyl ether was added, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropylated silica gel thin layer chromatography (developing solvent: methylene chloride / methanol = 100/1) to obtain the title compound (1.7 mg).
Compound 7-2 to Compound 7-7 were synthesized in the same manner as in Example 4 using the corresponding amine instead of 4- (2-aminoethyl) morpholine. These are shown in Table 7.

Example 5
2,6-Dimethylphenyl- {5- [4- (2-morpholin-4-ylethoxy) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine (Compound 8-1)
To a solution of compound 6-6 (28 mg), 2-morpholin-4-ylethanol (41 μL), and triphenylphosphine (44.5 mg) in tetrahydrofuran (1.0 mL) was added diethyl azodicarboxylate (40% toluene solution) (73.7 μL). ) Was added at room temperature and stirred at 50 ° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluent: ethyl acetate / methanol = 10/1) to give the title compound (23.0 mg).
Using the corresponding alcohol instead of 2-morpholin-4-ylethanol and using compound 6-6, 6-7, or 6-9, in the same manner as in Example 5, compound 8-2 to compound 8- 22 was synthesized. These are shown in Table 8.

Example 6
2,6-Dimethylphenyl- {5- [4- (2-piperazin-1-ylethoxy) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine hydrochloride (Compound 8-23)
To a solution of compound 8-11 (16 mg) in ethanol (1 mL) was added 41% hydrogen chloride / ethanol solution (1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (10 mg). This is shown in Table 8.

Example 7
2,6-Dimethylphenyl- {5- [3- (2-piperazin-1-ylethoxy) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine (Compound 8-24)
To a solution of compound 8-16 (68 mg) in ethanol (1 mL) was added 41% hydrogen chloride / ethanol solution (2 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by SCX ion column (International Solvent Technology, elution solvent: 2 mol / L ammonia / methanol solution) to obtain the title compound (38 mg). This is shown in Table 8.

Example 8
2- {4- [8- (2,6-Dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] phenoxy} -1-morpholin-4-ylethanone (Compound 9-1)
To a solution of compound 6-6 (30 mg) and potassium carbonate (37.6 mg) in N, N-dimethylformamide (1.0 mL) was added 2-bromo-1-morpholin-4-ylethanone (20 mg) at room temperature, and the mixture was heated at 60 ° C. Stir overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by aminopropylated silica gel thin layer chromatography (elution solvent: methylene chloride / methanol = 50/1) to obtain the title compound (3.8 mg).
Compound 9-3 and Compound 9-8 were synthesized using Compound 6-6 or Compound 6-7 using the corresponding alkylating agent instead of 2-bromo-1-morpholin-4-ylethanone. These are shown in Table 9.

Example 9
{4- [8- (2,6-Dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] phenoxy} acetic acid (Compound 9-2)
To a solution of compound 6-6 (51 mg) and N, N-diisopropylethylamine (21 μL) in N, N-dimethylformamide (0.5 mL) was added methyl bromoacetate (38 μL) at room temperature, and the mixture was stirred for 2 days under the same conditions. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by aminopropylated silica gel thin layer chromatography (elution solvent: methylene chloride / methanol = 9/1) to obtain the title compound (17.8 mg). This is shown in Table 9.

Example 10
Dibenzyl-3- [8- (2,6-dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] phenyl phosphate (Compound 9-4)
To a solution of compound 6-7 (60 mg) in acetonitrile (1.0 mL) and dimethyl sulfoxide (0.1 mL), carbon tetrabromide (301 mg), N, N-diisopropylethylamine (67 μL), 4-dimethylaminopyridine (2.2 mg) , Dibenzyl phosphite (59 μL) and tetrahydrofuran (0.5 mL) were added at −10 ° C. The reaction mixture was stirred for 25 minutes under the same conditions, and then warmed to room temperature. After stirring for 50 minutes, 0.5 mol / L potassium dihydrogen phosphate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent: methylene chloride / methanol = 20/1) to obtain the title compound (66.2 mg). This is shown in Table 9.

Example 11
Mono-3- [8- (2,6-dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] phenyl phosphate (Compound 9-5)
An ethanol suspension of compound 9-4 (20.3 mg) and 10% -palladium / carbon (50% water-containing product, 40 mg) was stirred at room temperature under a hydrogen atmosphere for 3.5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (8.8 mg). This is shown in Table 9.

Example 12
Dimethyl-3- [8- (2,6-dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] phenyl phosphate (Compound 9-6)
To a solution of compound 6-7 (30 mg) in acetonitrile (0.5 mL) and tetrahydrofuran (0.2 mL), carbon tetrabromide (151 mg), N, N-diisopropylethylamine (35 μL), 4-dimethylaminopyridine (1.1 mg) and Dimethyl phosphite (12 μL) was added at −10 ° C. The reaction mixture was stirred for 2 hours under the same conditions, and then warmed to room temperature. After stirring for 4 hours, 0.5 mol / L potassium dihydrogen phosphate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent: methylene chloride / methanol = 20/1) to obtain the title compound (30.8 mg). This is shown in Table 9.

Example 13
Diethyl-3- [8- (2,6-dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] phenyl phosphate (Compound 9-7)
To a solution of compound 6-7 (30 mg) in acetonitrile (0.5 mL) and dimethyl sulfoxide (0.2 mL), carbon tetrabromide (151 mg), N, N-diisopropylethylamine (35 μL), 4-dimethylaminopyridine (1.1 mg) And diethyl phosphite (13.5 μL) was added at 0 ° C. The reaction mixture was stirred for 15 minutes under the same conditions, and then warmed to room temperature. After stirring overnight, 0.5 mol / L potassium dihydrogen phosphate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent: ethyl acetate) to obtain the title compound (35.6 mg). This is shown in Table 9.

Example 14
4- [8- (2,6-Dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] benzonitrile (Compound 10-1)
Compound 6-4 (1.18 g), sodium cyanide (264 mg), tetrakis (triphenylphosphine) palladium (0) (155 mg) and copper (I) iodide (53 mg) in acetonitrile (10 mL), and tetrahydrofuran (5 mL) The suspension was stirred under reflux for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The residue was suspended in methylene chloride, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was suspended in ethyl acetate and hexane and collected by filtration to give the title compound (812 mg). This is shown in Table 10.

Example 15
[5- (4-Aminomethylphenyl) imidazo [1,5-a] pyrazin-8-yl] -2,6-dimethylphenylamine (Compound 10-2)
A suspension of compound 10-1 (30 mg) and 10% -palladium / carbon (50% water-containing product, 50 mg) in methanol (0.6 mL) and methylene chloride (0.4 mL) was stirred overnight at room temperature under a hydrogen atmosphere. After removing insolubles by filtration, the residue was subjected to SCX ion column (made by International Solvent Technology, elution solvent: 2 mol / L ammonia / methanol solution) and aminopropylated silica gel thin layer chromatography (developing solvent: methylene chloride / methanol = 50 / Purified in 1). The eluate was suspended in methylene chloride, and the insoluble material was removed by filtration to obtain the title compound (1.3 mg). This is shown in Table 10.

Example 16
4- [8- (2,6-Dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] benzoic acid (Compound 10-3)
Sodium hydroxide (38 mg) was added to a solution of compound 10-1 (30 mg) in tetrahydrofuran (0.3 mL), ethanol (0.5 mL), and water (0.5 mL), and the mixture was stirred at 65 ° C. overnight. The mixture was neutralized with 1 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was extracted with a 1 mol / L aqueous sodium hydroxide solution, the aqueous layer was acidified with 1 mol / L hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in methylene chloride, and the insoluble material was collected by filtration to give the title compound (10.5 mg). This is shown in Table 10.

Example 17
4- [8- (2,6-Dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] benzamide (Compound 10-4)
To a solution of compound 10-1 (30 mg) in dimethyl sulfoxide (0.5 mL) and ethanol (0.5 mL) were added 5 mol / L aqueous sodium hydroxide solution (400 μL) and 30% aqueous hydrogen peroxide (200 μL). After stirring for 1 hour under the same conditions, 30% hydrogen peroxide (200 μL) was added, and the mixture was stirred for 1.5 hours. 2 mol / L hydrochloric acid (1 mL) was added, and the precipitate was collected by filtration to give the title compound (12 mg). This is shown in Table 10.

Example 18
4- [8- (2,6-Dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] ethyl benzoate (Compound 10-5)
A 41% hydrogen chloride / ethanol solution (0.36 mL) was added to an ethanol suspension of compound 10-1 (385 mg), and the mixture was stirred overnight. Furthermore, 41% hydrogen chloride / ethanol solution (10.0 mL) was added and stirred overnight. The reaction mixture was neutralized with 5 mol / L aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: hexane / ethyl acetate = 2/1) to give the title compound (271 mg). This is shown in Table 10.

Example 19
{4- [8- (2,6-Dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] phenyl} methanol (Compound 10-6)
To a solution of compound 10-5 (257 mg) in tetrahydrofuran (6 mL) was added lithium aluminum hydride (48 mg) under ice cooling, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, the insoluble material was removed by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (203 mg). This is shown in Table 10.

Example 20
[5- (4-Bromomethylphenyl) imidazo [1,5-a] pyrazin-8-yl] -2,6-dimethylphenylamine (Compound 10-7)
Carbon tetrabromide and triphenylphosphine were added to a methylene chloride solution of compound 10-6 (114 mg), and the mixture was stirred at room temperature for 2.5 hours. The precipitate was collected by filtration to give the title compound (22 mg). This is shown in Table 10.

Example 21
4- [8- (2,6-Dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] benzaldehyde (Compound 10-8)
Manganese dioxide (102 mg) was added to a methylene chloride solution of compound 10-6 (30 mg), and the mixture was stirred at room temperature for 2 days. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent: hexane / ethyl acetate = 1/4) to obtain the title compound (24.8 mg). This is shown in Table 10.

Example 22
{4- [8- (2,6-Dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] phenyl} morpholin-4-ylmethanone (Compound 10-9)
To a solution of compound 10-3 (20 mg) in N, N-dimethylformamide (0.5 mL), morpholine (5.3 mg), 1-hydroxybenzotriazole monohydrate (9.4 mg), and 1-ethyl-3- ( 3-Dimethylaminopropyl) carbodiimide hydrochloride (11.8 mg) was added, and the mixture was stirred overnight at room temperature. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by aminopropylated silica gel thin layer chromatography (developing solvent: methylene chloride / methanol = 50/1) to obtain the title compound (9.7 mg).
Compound 10-10 to Compound 10-13 were synthesized in the same manner as in Example 22 using the corresponding amine instead of morpholine. These are shown in Table 10.

Reference Example 8
5-Bromo-1- (4-methoxybenzyl) -1H-pyrazin-2-one Under argon atmosphere, 5-bromo-1H-pyrazin-2-one (1.52 g) N, N-dimethylformamide (16 mL) and Sodium hydride (60%, 400 mg) was added to a tetrahydrofuran (4 mL) solution under ice-cooling, and the mixture was stirred for 30 minutes under the same conditions. 4-Methoxybenzyl chloride (1.30 mL) and i-n-tetrabutylammonium iodide (321 mg) were added to the reaction mixture, followed by stirring at room temperature for 30 minutes and further stirring at 70 ° C. for 1 hour. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and 10% brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution solvent: ethyl acetate / hexane = 1/1) to obtain the title compound (1.47 g).
¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.73 (3H, s), 4.97 (2H, s), 6,92 (2H, d, J = 8.8 Hz), 7.34 (2H, d, J = 8.8 Hz), 7.88 (1H, s), 8.18 (1H, s)

Reference Example 9
5-Bromo-7- (4-methoxybenzyl) -7H-imidazo [1,5-a] pyrazin-8-one Reference Example 8 (1.45 g) and p-toluenesulfonylmethyl isocyanide (1.07 g) in tetrahydrofuran (7.5 The solution was added dropwise to a suspension of sodium hydride (60%, 439 mg) in tetrahydrofuran (7.5 mL) at 0 ° C. under an argon atmosphere. After stirring for 30 minutes under the same conditions, the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and 10% brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel flash column chromatography (elution solvent: ethyl acetate) to obtain the title compound (1.56 g).
¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.72 (3H, s), 4.94 (2H, s), 6,90 (2H, d, J = 8.8 Hz), 7.32 (2H, d, J = 8.8 Hz), 7.43 (1H, s), 7.94 (1H, s), 8.32 (1H, s)

Reference Example 10
5-Bromo-7H-imidazo [1,5-a] pyrazin-8-one A solution of Reference Example 9 (1.51 g) and anisole (8.8 mL) in trifluoroacetic acid (21 mL) was cooled with trifluoromethanesulfonic acid (21 mL). (4.8 mL) was added, and the mixture was stirred at room temperature for 30 minutes, and further stirred at 50 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate. The precipitate was collected by filtration, suspended in ethyl acetate (20 mL), and stirred under reflux for 1 hour. The precipitate was collected by filtration to give the title compound (747 mg).
¹ H-NMR (DMSO-d ₆ ) δ ppm: 7.03 (1H, s), 7.90-7.95 (1H, m), 8.30-8.35 (1H, s), 11.02 (1H, brs)

Example 23
(5-Bromoimidazo [1,5-a] pyrazin-8-yl) -2,6-dimethylphenylamine (Compound 11-1)
A suspension of Reference Example 10 (820 mg) in phosphorus oxychloride (8.6 mL) was stirred under reflux for 5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and further azeotropically distilled off with toluene to give a crude product of 5-bromo-8-chloroimidazo [1,5-a] pyrazine.
To a solution of 2,6-dimethylaniline (1.58 mL) in tetrahydrofuran (2 mL) was added 1 mol / L sodium bis (trimethylsilyl) amide / tetrahydrofuran solution (23 mL), and the mixture was stirred at 60 ° C. for 30 minutes. After cooling to room temperature, a solution of 5-bromo-8-chloroimidazo [1,5-a] pyrazine in tetrahydrofuran (1.5 mL) was added dropwise to the reaction mixture and stirred at 60 ° C. for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and 10% brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel flash column chromatography (elution solvent: ethyl acetate) to obtain the title compound (845 mg). This is shown in Table 11.

Example 24
[5- (3,4-Dimethoxyphenyl) imidazo [1,5-a] pyrazin-8-yl] -2,6-dimethylphenylamine (Compound 11-2)
Compound 11-1 (54 mg), 3,4-dimethoxyphenylboronic acid (32 mg), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (7 mg) and potassium carbonate (32.6 mg) ) In N, N-dimethylformamide (50 μL), water (250 μL), and toluene (250 μL) were stirred at 90 ° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by aminopropylated silica gel flash column chromatography (elution solvent: ethyl acetate / hexane = 1/1) to obtain the title compound (53 mg).
Compound 11-3 to Compound 11-15 were synthesized in the same manner as in Example 24 using the corresponding boronic acid derivative instead of 3,4-dimethoxyphenylboronic acid. These are shown in Table 11.

Example 25
5- [8- (2,6-Dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] thiophene-2-carbaldehyde (Compound 11-16)
Compound 11-1 (254 mg), 5-tributylstannylthiophene-2-carbaldehyde (418 mg), and bis (triphenylphosphine) palladium (II) chloride (56.2 mg) were suspended in 1,4-dioxane (3 mL). It became cloudy and stirred under reflux overnight. After cooling to room temperature, ethyl acetate was added to the reaction mixture, washed with water and 10% brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution solvent: ethyl acetate) to obtain the title compound (243 mg). This is shown in Table 11.

Example 26
2,6-Dimethylphenyl- {5- [4- (4-methylpiperazin-1-ylmethyl) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine (Compound 12-1)
To a solution of compound 10-7 (22.3 mg) and N-methylpiperazine (10 μL) in tetrahydrofuran (0.5 mL) was added potassium carbonate (10 mg), and the mixture was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by aminopropylated silica gel thin layer chromatography (developing solvent: hexane / ethyl acetate = 1/1) to obtain the title compound (17.6 mg).
Compound 12-2 was synthesized in the same manner as in Example 26 using dimethylamine instead of N-methylpiperazine. These are shown in Table 12.

Example 27
[5- (3-Dimethylaminomethylphenyl) imidazo [1,5-a] pyrazin-8-yl] -2,6-dimethylphenylamine hydrochloride (Compound 12-3)
Titanium tetraisopropoxide (40 μL) was added to a suspension of compound 11-15 (23 mg), dimethylamine hydrochloride (11 mg), and triethylamine (19 μL) in methanol (0.5 mL), and the mixture was stirred at room temperature overnight. Sodium tetrahydroborate (3.8 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on aminopropylated silica gel (elution solvent: ethyl acetate) to give [5- (3-dimethylaminomethylphenyl) imidazo [1,5-a] pyrazin-8-yl] -2,6- Dimethylphenylamine was obtained.
After dissolving [5- (3-dimethylaminomethylphenyl) imidazo [1,5-a] pyrazin-8-yl] -2,6-dimethylphenylamine in ethyl acetate, a 4 mol / L hydrogen chloride / ethyl acetate solution ( 50 μL) was added, and the precipitate was collected by filtration to give the title compound (24 mg).
Compound 12-4 to Compound 12-14 were synthesized in the same manner as in Example 27 using Compound 10-8 or Compound 11-15 using the corresponding amine instead of dimethylamine hydrochloride. These are shown in Table 12.

Example 28
[5- (5-Dimethylaminomethylthiophen-2-yl) imidazo [1,5-a] pyrazin-8-yl] -2,6-dimethylphenylamine hydrochloride (Compound 12-15)
Titanium tetraisopropoxide (75 μL) was added to a suspension of compound 11-16 (43 mg), dimethylamine hydrochloride (20 mg), and triethylamine (34 μL) in methanol (1.0 mL), and the mixture was stirred at room temperature overnight. Sodium tetrahydroborate (6.9 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on aminopropylated silica gel (elution solvent: ethyl acetate), and [5- (5-dimethylaminomethylthiophen-2-yl) imidazo [1,5-a] pyrazin-8-yl]- 2,6-dimethylphenylamine was obtained.
After dissolving [5- (5-dimethylaminomethylthiophen-2-yl) imidazo [1,5-a] pyrazin-8-yl] -2,6-dimethylphenylamine in ethyl acetate, 4 mol / L hydrogen chloride / Ethyl acetate solution (53 μL) was added, and the precipitate was collected by filtration to give the title compound (28 mg).
Compound 12-16 and Compound 12-17 were synthesized in the same manner as Example 28 using the corresponding amine instead of dimethylamine hydrochloride. These are shown in Table 12.

Example 29
[5- (4-Dimethylaminomethylphenyl) imidazo [1,5-a] pyrazin-8-yl] -2,6-dimethylphenylamine hydrochloride (Compound 13-1)
To a solution of compound 12-2 (37 mg) in ethyl acetate (1.0 mL) was added 4 mol / L hydrogen chloride / ethyl acetate solution (0.1 mL), and the mixture was stirred for 10 minutes. The precipitate was collected by filtration to give the title compound (45 mg).
In the same manner as in Example 29 except that compound 8-2, 8-10, 10-11, 8-13, 8-6, 8-12, or 12-1 was used instead of compound 12-2, compound 13 -2 to Compound 13-8 were synthesized. These are shown in Table 13.

Reference Example 11
1-Benzyl-1H-imidazole-4-carboxamide To a suspension of methyl 1-benzyl-1H-imidazole-4-carboxylate (2.3 g) in 28% aqueous ammonia (14 mL) was added ammonium chloride (175 mg). . The reaction mixture was stirred at 100 ° C. overnight, and the precipitate was collected by filtration to give the title compound (1.9 g).
¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.22 (2H, s), 7.00-7.10 (1H, m), 7.20-7.45 (6H, m), 7.67 (1H, d, J = 1.3 Hz), 7.81 (1H, d, J = 1.3Hz)

Reference Example 12
2-Benzyl-8-oxo-6-phenyl-7,8-dihydroimidazo [1,5-a] pyrazinium bromide (Compound 14-1)
To a suspension of Reference Example 11 (1.2 g) in N, N-dimethylformamide (2.0 mL) and acetonitrile (10.0 mL), phenacyl bromide (1.3 g) was added and stirred at 90 ° C. for 20 hours.
After cooling to room temperature, the precipitate was collected by filtration to obtain the title compound (1.5 g).
Compound 14-2 to Compound 14-8 were synthesized in the same manner as in Reference Example 12 using the corresponding 2-haloketone derivative instead of phenacyl bromide. These are shown in Table 14.

Reference Example 13
6-Phenyl-7H-imidazo [1,5-a] pyrazin-8-one (Compound 15-1)
A mixture of compound 14-1 (1.1 g) and imidazole (5.0 g) was stirred at 175 ° C. for 8 hours. The reaction mixture was cooled to 100 ° C., poured into water, and the precipitate was collected by filtration to give the title compound (407 mg).
Compound 15-2 to compound 15-8 were synthesized in the same manner as in Reference Example 13 using compounds 14-2 to 14-8 instead of compound 14-1. These are shown in Table 15.

Example 30
Phenyl- (6-phenylimidazo [1,5-a] pyrazin-8-yl) amine (Compound 16-1)
A suspension of compound 15-1 (51 mg) in phosphorus oxychloride (450 μL) was stirred under reflux for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and further azeotropically distilled off with toluene to obtain a crude product of 8-chloro-6-phenylimidazo [1,5-a] pyrazine.
A solution of 8-chloro-6-phenylimidazo [1,5-a] pyrazine and aniline (48 μL) in tetrahydrofuran (1.0 mL) was stirred at 60 ° C. overnight. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel flash column chromatography (eluent: ethyl acetate / hexane = 2/1) to give the title compound (7.8 mg).
Compounds 16-2 to 16-4 were synthesized in the same manner as Example 30 using aniline derivatives instead of aniline. These are shown in Table 16.

Example 31
2-Chloro-6-methylphenyl- (6-phenylimidazo [1,5-a] pyrazin-8-yl) amine (Compound 16-5)
A suspension of compound 15-1 (160 mg) in phosphorus oxychloride (1.4 mL) was stirred under reflux for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a crude product of 8-chloro-6-phenylimidazo [1,5-a] pyrazine.
To a solution of 2-chloro-6-methylaniline (41 μL) in tetrahydrofuran (2.8 mL) was added 1 mol / L sodium bis (trimethylsilyl) amide / tetrahydrofuran solution (720 μL) at room temperature, and the mixture was stirred for 30 minutes under reflux. After cooling to room temperature, a suspension of 8-chloro-6-phenylimidazo [1,5-a] pyrazine in tetrahydrofuran (5.6 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour under reflux. After cooling at room temperature, 2-chloro-6-methylaniline (41 μL) and 1 mol / L sodium bis (trimethylsilyl) amide / tetrahydrofuran solution (720 μL) were added to the reaction mixture, followed by stirring for 1 hour under reflux. Acetic acid (4.2 mL) was added at room temperature, and the reaction mixture was concentrated under reduced pressure. To this residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel flash column chromatography (elution solvent: ethyl acetate / hexane = 2/1) to obtain the title compound (43.5 mg).
Compound 16-6 to Compound 16-13 were synthesized in the same manner as Example 31 using Compound 15-2 to Compound 15-8 using aniline derivatives instead of 2-chloro-6-methylaniline. These are shown in Table 16.

Example 32
3- [8- (2,6-Dimethylphenylamino) imidazo [1,5-a] pyrazin-6-yl] phenol (Compound 17-1)
Under ice cooling, a 2 mol / L boron tribromide methylene chloride solution (29 μL) was added to a suspension of compound 16-7 (14 mg) in methylene chloride (1 mL), and the mixture was stirred for 30 minutes under the same conditions. A 2 mol / L boron tribromide methylene chloride solution (29 μL) was added at room temperature, and the mixture was stirred for 2 hours under the same conditions. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (elution solvent: methylene chloride / methanol = 9/1) to obtain the title compound (10.6 mg).
Compound 17-2 and Compound 17-6 were synthesized in the same manner as Example 32 using Compound 16-9 or Compound 16-11 instead of Compound 16-7. These are shown in Table 17.

Example 33
Ethyl 4- [8- (2-chloro-6-methylphenylamino) imidazo [1,5-a] pyrazin-6-yl] benzoate (compound 17-3) and 4- [8- (2-chloro- 6-Methylphenylamino) imidazo [1,5-a] pyrazin-6-yl] benzamide (Compound 17-4)
41% hydrogen chloride / ethanol solution (6.0 mL) was added to compound 16-10 (141 mg), and the mixture was stirred for 17.5 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, the insoluble material was collected by filtration, and washed with ethyl acetate to give the title compound (Compound 17-3) (144 mg).
The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (Compound 17-4) (19 mg).
These are shown in Table 17.

Example 34
4- [8- (2-Chloro-6-methylphenylamino) imidazo [1,5-a] pyrazin-6-yl] benzoic acid (Compound 17-5)
To a solution of compound 17-3 (139 mg) in ethanol (3.4 mL) was added 1 mol / L aqueous sodium hydroxide solution (1.71 mL), and the mixture was stirred for 37 hours under reflux. After cooling to room temperature, 1 mol / L hydrochloric acid (1.71 mL) was added to the reaction mixture, and the precipitate was collected by filtration to give the title compound (136 mg). This is shown in Table 17.

Example 35
2-Chloro-6-methylphenyl- {6- [3- (2-morpholin-4-ylethoxy) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine (Compound 18-1)
To a solution of compound 17-1 (10 mg), 2-morpholin-4-ylethanol (14 μL), and triphenylphosphine (14 mg) in tetrahydrofuran (1.0 mL) was added diethyl azodicarboxylate (40% toluene solution) (23 μL). The mixture was added under ice cooling and stirred at room temperature for 92 hours. Triphenylphosphine (14 mg) and diethyl azodicarboxylate (40% toluene solution) (23 μL) were added to the reaction mixture, followed by stirring at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by aminopropylated silica gel thin layer chromatography (developing solvent: ethyl acetate) to obtain the title compound (5.3 mg).
Compound 18-2 to Compound 18-4 were synthesized in the same manner as in Example 35 using Compound 17-1 or 17-2 using the corresponding alcohol instead of 2-morpholin-4-ylethanol. These are shown in Table 18.

Example 36
{4- [8- (2-Chloro-6-methylphenylamino) imidazo [1,5-a] pyrazin-6-yl] phenyl} morpholin-4-ylmethanone (Compound 19-1)
To a solution of compound 17-5 (21 mg) in N, N-dimethylformamide (1.0 mL) was added morpholine (5.8 μL), 1-hydroxybenzotriazole monohydrate (11 mg), and 1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide hydrochloride (13 mg) was added, and the mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel thin layer chromatography (developing solvent: methylene chloride / methanol = 50/1) to give the title compound (11 mg). It was.
Compound 19-2 to Compound 19-5 were synthesized in the same manner as in Example 36 using the corresponding amine instead of morpholine. These are shown in Table 19.

Example 37
2-Chloro-6-dimethylphenyl- [6- (4-morpholin-4-ylphenyl) imidazo [1,5-a] pyrazin-8-yl] amine (Compound 20-1)
Compound 16-6 (24 mg), morpholine (6 μL), tris (dibenzylideneacetone) dipalladium (0) (14 mg), sodium tert-butoxide (7 mg) and (R)-(+)-2,2′-bis A toluene suspension of (diphenylphosphino) -1,1′-binaphthyl (BINAP) (27 mg) was stirred at 100 ° C. for 13 hours under an argon atmosphere. After cooling to room temperature, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (RP-18 WF254, developing solvent: methylene chloride / methanol = 10/1) to obtain the title compound (0.4 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.35 (3H, s), 3.15-3.25 (4H, m), 3.80-3.90 (4H, m), 6.85-7.00 (2H, m), 7.05-7.40 (5H , m), 7.65-7.75 (2H, m), 7.76 (1H, s), 8.10 (1H, s)

Example 38
8- (2-Chloro-6-methylphenylamino) -6-phenylimidazo [1,5-a] pyrazine-3-carbaldehyde (Compound 20-2)
Process 1
To a solution of tert-butyl 2-chloro-6-methylphenyl- (6-phenylimidazo [1,5-a] pyrazin-8-yl) carbamate compound 16-5 (34 mg) in tetrahydrofuran (1.0 mL) was added 1 mol / L sodium bis (trimethylsilyl) amide / tetrahydrofuran solution (121 μL), di-tert-butyl carbonate (32 mg), and 4-dimethylaminopyridine (6.6 mg) were added, and the mixture was stirred at 75 ° C. for 2 hours. After cooling at room temperature, di-tert-butyl carbonate (11 mg) was added to the reaction mixture, and the mixture was stirred at 75 ° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent: ethyl acetate / hexane = 2/1) to give 2-chloro-6-methylphenyl- (6-phenylimidazo [1,5-a] pyrazine-8- Yl) tert-butyl carbamate (19.2 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm: 1.49 (9H, s), 2.31 (3H, s), 7.15-7.25 (2H, m), 7.25-7.40 (4H, m), 7.65-7.70 (2H, m ), 7.71 (1H, s), 8.08 (1H, d, J = 0.6Hz), 8.24 (1H, s)
Process 2
2-chloro-6-methylphenyl- (3-formyl-6-phenylimidazo [1,5-a] pyrazin-8-yl) carbamate tert-butyl Diisopropylamine (14 μL) in tetrahydrofuran (1.3 mL) under argon atmosphere ) 2.64 mol / L-n-butyllithium (hexane solution) (26 μL) was added to the solution at −78 ° C. After stirring at 0 ° C. for 15 minutes and cooling to −78 ° C., the reaction mixture was mixed with 2-chloro-6-methylphenyl- (6-phenylimidazo [1,5-a] pyrazin-8-yl) carbamic acid tert- A solution of butyl (18.5 mg) in tetrahydrofuran (250 μL) was added, and the mixture was stirred for 15 minutes under the same conditions. N, N-dimethylformamide (16 μL) was added to the reaction mixture, and the mixture was stirred under the same conditions for 30 minutes and at room temperature for 20 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent: ethyl acetate / hexane = 2/3) to give 2-chloro-6-methylphenyl- (3-formyl-6-phenylimidazo [1,5-a]. Pyrazine-8-yl) carbamate tert-butyl (8.5 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm: 1.50 (9H, s), 2.35 (3H, s), 7.20-7.25 (2H, m), 7.30-7.45 (4H, m), 7.70-7.80 (2H, m ), 7.95-8.00 (1H, m), 9.58 (1H, d, J = 0.6Hz), 10.11 (1H, s)
Process 3
8- (2-chloro-6-methylphenylamino) -6-phenylimidazo [1,5-a] pyrazine-3-carbaldehyde 2-chloro-6-methylphenyl- (3-formyl-6-phenylimidazo [ 1,5-a] pyrazin-8-yl) carbamate tert-butyl (8.5 mg) was dissolved in 30% trifluoroacetic acid / methylene chloride solution (1.0 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel thin layer chromatography (developing solvent: ethyl acetate / hexane = 2/3) to obtain the title compound (6.5 mg).
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.29 (3H, s), 7.30-7.45 (5H, m), 7.45-7.55 (1H, m), 7.65-7.80 (2H, m), 8.27 (1H , brs), 9.04 (1H, s), 9.81 (1H, s), 10.02 (1H, s)

Example 39
[8- (2-Chloro-6-methylphenylamino) -6-phenylimidazo [1,5-a] pyrazin-3-yl] methanol (Compound 20-3)
Sodium tetrahydroborate (2.1 mg) and methanol (0.1 mL) were added to a solution of compound 20-2 (3.6 mg) in tetrahydrofuran (0.5 mL), and the mixture was stirred at room temperature for 45 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel thin layer chromatography (developing solvent: methylene chloride / methanol = 10/1) to obtain the title compound (0.3 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.17 (1H, s), 2.36 (3H, s), 5.07 (2H, s), 6.95-7.15 (1H, m), 7.15-7.50 (7H, m), 7.75-7.90 (2H, m), 7.96 (1H, d, J = 0.6Hz)

Test example 1
c-src tyrosine kinase inhibitory action test
1) Cloning, expression, and purification of c-src protein The human c-src kinase domain (SER251-PHE523) was obtained from human placenta cDNA using the PCR (polymerase chain reaction) method. To Nde and XhoI sites. Furthermore, this human c-src kinase domain is included in the BAC-TO-BAC (registered trademark) baculovirus expression system (GIBCO BRL) with the His tag gene of pET-19b bound to its 5 'end. Vector pFASTBAC1. This plasmid DNA was transduced into competent cells DH10BAC included in the baculovirus expression system to produce recombinant virus DNA. Further, recombinant virus (culture supernatant) was obtained by transfecting recombinant virus DNA into Sf-9 cells (Invitrogen).
High Five (registered trademark) insect cells (Invitrogen) infected with the recombinant virus were collected and lysed by sonication. After centrifuging the soluble fraction, the supernatant was mixed with TALON (registered trademark) metal affinity resin (CLONTECH), and the His-tag fusion protein of the c-src kinase domain was adsorbed to the resin. After washing the resin several times, the His-tag fusion protein of the c-src kinase domain was eluted with a buffer containing imidazole.

2) c-src tyrosine kinase inhibition assay The c-src inhibitory activity of the test compound was measured by a coupled enzyme assay using a spectrophotometer. Various concentrations of test compounds dissolved in 10 nmol / L c-src kinase domain protein and dimethyl sulfoxide were added in 0.1 mol / L HEPES buffer (pH 7.6, 20 mmol / L MgCl2, 2.5 mmol / L phosphoenolpyruvate, 0.2 mmol / L NADH, 150 μg / mL pyruvate kinase, 50 μg / mL lactate dehydrogenase, 0.5 mmol / L c-src peptide) and left at 30 ° C. for 10 minutes. c-src peptide (amino acid sequence: AEEEIYGEFEAKKKK) was used as a phosphate group acceptor substrate for c-src tyrosine kinase catalysis. The enzyme reaction was started by adding 50 μmol / L of ATP, and the decrease in absorption (rate V (mOD / min)) at 340 nm per unit time was measured with a spectrophotometer set at 30 ° C. The velocity value V (mOD / min) with respect to the inhibitor concentration was input to enzyme velocity analysis software Plate Ki (Bio Kin, Ltd.), and the Ki value was calculated. These results are shown in Table 20.

Test example 2
Lck tyrosine kinase inhibitory action test
1) Cloning, expression and purification of Lck protein The human Lck kinase domain (Gln225-Pro509) was obtained from the human spleen Marathon-Ready (registered trademark) cDNA (CLONTECH) using the PCR method, pET-19b expression vector. Cloning into Nde and XhoI sites of (Novagen). Furthermore, this human Lck kinase domain is a vector included in the BAC-TO-BAC (registered trademark) baculovirus expression system (GIBCO BRL) with the His tag gene of pET-19b linked to its 5 'end. Incorporated into pFASTBAC1. This plasmid DNA was transduced into the competent cell DH10BAC contained in the baculovirus expression system to produce recombinant virus DNA. Further, recombinant virus (culture supernatant) was obtained by transfecting recombinant virus DNA into Sf-9 cells (Invitrogen).
High Five (registered trademark) insect cells (Invitrogen) infected with the recombinant virus were collected and lysed by sonication. After the soluble fraction was centrifuged, the supernatant was mixed with TALON (registered trademark) metal affinity resin (CLONTECH), and the His tag fusion protein of the Lck kinase domain was adsorbed to the resin. After washing the resin several times, the His tag fusion protein of the Lck kinase domain was eluted with a buffer containing imidazole.

2) Lck tyrosine kinase inhibition assay The Lck inhibitory activity of the test compound was measured by a coupled enzyme assay using a spectrophotometer. Various concentrations of test compounds dissolved in 10 nmol / L Lck kinase domain protein and dimethyl sulfoxide were added in 0.1 mol / L HEPES buffer (pH 7.6, 20 mmol / L MgCl2, 2.5 mmol / L phosphoenolpyruvate, 0. 2 mmol / L NADH, 150 μg / mL pyruvate kinase, 50 μg / mL lactate dehydrogenase, 0.5 mmol / L c-src peptide) at 30 ° C. for 10 minutes. The c-src peptide (amino acid sequence: AEEEIYGEFEAKKKK) was used as a phosphate group acceptor substrate for Lck tyrosine kinase catalysis. The enzyme reaction was started by adding 50 μmol / L of ATP, and the decrease in absorption (rate V (mOD / min)) at 340 nm per unit time was measured with a spectrophotometer set at 30 ° C. The velocity value V (mOD / min) with respect to the inhibitor concentration was input to enzyme velocity analysis software Plate Ki (Bio Kin, Ltd.), and the Ki value was calculated. These results are shown in Table 21.

  Since the compound of the present invention has an excellent protein tyrosine kinase inhibitory action, it is useful as a therapeutic or prophylactic agent for diseases caused by abnormal protein tyrosine kinases, particularly cancer, bone diseases (for example, osteoporosis, paget disease, Hypercalcemia, osteoarthritis, etc.), Parkinson's disease, epilepsy, cerebral edema, acute cerebral infarction, cerebral vasospasm, diseases involving T cells (eg, psoriasis, atopic dermatitis, rheumatoid arthritis, systemic) It is suitable as a therapeutic or prophylactic agent for lupus erythematosus, nephrotic syndrome, graft-versus-host disease, rejection due to organ transplantation, and the like.

Claims (19)

Formula (I):
[Where,
R ¹ is a hydrogen atom or a lower alkyl group;
R ² is a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower acyl group;
R ³ and R ⁴ are each independently the following a) to e):
a) a hydrogen atom,
b) a halogen atom,
c) a lower alkyl group,
d) a phenyl group which is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of X ¹ , X ² and X ³ , or e) a heteroaryl group,
Here, X ¹ , X ² and X ³ are each independently the following a) to m):
a) a halogen atom,
b) a lower alkyl group,
c) a halo lower alkyl group,
d) a hydroxy lower alkyl group,
e) a lower alkoxy group,
f) a halo lower alkoxy group,
g) hydroxyl group,
h) -OP (O) (OR 6) 2,
i) a nitro group,
^{j) -A 1 -NR 7 R 8} ,
^k) -A 2 ^-R 9,
l) —O—A ³ —R ¹⁰ , or m) —O—A ⁴ —O—A ⁵ —R ¹¹ ;
R ⁵ represents the following a) to c):
a) a phenyl group which is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of X ⁴ , X ⁵ and X ⁶ ;
b) a heteroaryl group, or c) an aralkyl group,
Here, X ⁴ , X ⁵ and X ⁶ each independently represent a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a hydroxyl group or a cyano group, or X ⁴ , X ⁵ and X 6 If two adjacent of ^6, they are bonded to - _(CH 2) n-is formed, wherein, n represents an integer of 3-5;
R ⁶ is a hydrogen atom, a lower alkyl group or an aralkyl group;
R ⁷ and R ⁸ are each independently the following a) to d):
a) a hydrogen atom,
b) a lower alkyl group,
c) a group consisting of: a lower alkyl group substituted with a group selected from a hydroxyl group, an amino group, a lower alkylamino group, a di-lower alkylamino group and a cyclic amino group, or d) an unsubstituted group or a group consisting of: Represents a phenyl group substituted with 1 to 3 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a hydroxyl group and a cyano group,
Alternatively, R ⁷ and R ⁸ together with the nitrogen atom to which they are attached are unsubstituted or from the group consisting of: a lower alkyl group, a hydroxyl group, a hydroxy lower alkyl group, a lower acyl group, and a lower alkoxycarbonyl group Forming a cyclic amino group substituted with a selected group;
R ⁹ is a formyl group, a carboxy group, a lower alkoxycarbonyl group, a cyano group, or —C (O) NR ⁷ R ⁸ ;
R ¹⁰ is a carboxy group, a lower alkoxycarbonyl group, —C (O) NR ⁷ R ⁸ , —NR ⁷ R ⁸ or a heterocyclyl group;
R ¹¹ is a di-lower alkylamino group or a cyclic amino group;
A ¹ is a bond or a C _1-6 alkylene group;
A ² is a bond, a C _1-6 alkylene group or a C _2-6 alkenylene group;
A ³ is a C _1-6 alkylene group;
A ⁴ and A ⁵ are each independently a C _2-4 alkylene group], a prodrug thereof, or a pharmaceutically acceptable salt thereof. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R ¹ is a hydrogen atom. The compound or pharmacologically acceptable salt thereof according to claim ² , wherein R ² is a hydrogen atom. A phenyl group in which one of R ³ and R ⁴ is a hydrogen atom and the other is unsubstituted or substituted with ^{1 to 3} groups independently selected from the group consisting of X ¹ , X ² and X ³ Or a heteroaryl group, wherein X ¹ , X ² and X ³ are as defined in claim 1, or a pharmaceutically acceptable salt thereof. A phenyl group in which one of R ³ and R ⁴ is a hydrogen atom and the other is unsubstituted or substituted with ^{1 to 3} groups independently selected from the group consisting of X ¹ , X ² and X ³ Or a heteroaryl group,
Here, X ¹ , X ² and X ³ are each independently the following a) to h):
a) a halogen atom,
b) a lower alkyl group,
c) a lower alkoxy group,
d) a hydroxyl group,
^{e) -A 1 -NR 7 R 8} ,
f) R ⁹ ,
g) —O—A ³ —R ¹⁰ , or h) —O—A ⁴ —O—A ⁵ —R ¹¹ ;
R ⁵ is unsubstituted or a group consisting of the following: a phenyl group substituted with 1 to 3 groups selected from a halogen atom, a lower alkyl group, a halo lower alkyl group and a lower alkoxy group;
R ⁷ and R ⁸ are each independently the following a) to c):
a) a hydrogen atom,
b) a lower alkyl group, or c) a group consisting of: a lower alkyl group substituted with a group selected from an amino group, a lower alkylamino group, a di-lower alkylamino group and a cyclic amino group,
Or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a cyclic amino group that is unsubstituted or substituted with a lower alkyl group;
R ⁹ is —C (O) NR ⁷ R ⁸ ;
R ¹⁰ is —NR ⁷ R ⁸ or a heterocyclyl group;
R ¹¹ is a di-lower alkylamino group or a cyclic amino group;
A ¹ is a bond or a C _1-6 alkylene group;
A ³ is a C _1-6 alkylene group;
The compound or pharmacologically acceptable salt thereof according to claim 3, wherein A ⁴ and A ⁵ are each independently a C _2-4 alkylene group. General formula (II):
[Where,
R ⁵ is unsubstituted or a phenyl group substituted with 1 to 3 groups selected from the group consisting of: a halogen atom, a lower alkyl group, a halo lower alkyl group and a lower alkoxy group;
X ¹⁰ is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group;
X ²⁰ represents the following a) to d):
^{a) -A 1 -NR 7 R 8} ,
b) -C (O) NR < ⁷ > R < ⁸ >,
c) —O—A ³ —R ¹⁰ , or d) —O—A ⁴ —O—A ⁵ —R ¹¹ ;
R ⁷ and R ⁸ are each independently the following a) to c):
a) a hydrogen atom,
b) a lower alkyl group, or c) a group consisting of: a lower alkyl group substituted with a group selected from an amino group, a lower alkylamino group, a di-lower alkylamino group and a cyclic amino group,
Or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a cyclic amino group that is unsubstituted or substituted with a lower alkyl group;
R ¹⁰ is —NR ⁷ R ⁸ or a heterocyclyl group;
R ¹¹ is a di-lower alkylamino group or a cyclic amino group;
A ¹ is a bond or a C _1-6 alkylene group;
A ³ is a C _1-6 alkylene group;
A ⁴ and A ⁵ are each independently a C _2-4 alkylene group] or a pharmacologically acceptable salt thereof. General formula (III):
[Where,
R ⁵ is unsubstituted or a phenyl group substituted with 1 to 3 groups selected from the group consisting of: a halogen atom, a lower alkyl group, a halo lower alkyl group and a lower alkoxy group;
X ¹⁰ is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group;
X ²⁰ represents the following a) to d):
^{a) -A 1 -NR 7 R 8} ,
b) -C (O) NR < ⁷ > R < ⁸ >,
c) —O—A ³ —R ¹⁰ , or d) —O—A ⁴ —O—A ⁵ —R ¹¹ ;
R ⁷ and R ⁸ are each independently the following a) to c):
a) a hydrogen atom,
b) a lower alkyl group, or c) a group consisting of: a lower alkyl group substituted with a group selected from an amino group, a lower alkylamino group, a di-lower alkylamino group and a cyclic amino group,
Or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a cyclic amino group that is unsubstituted or substituted with a lower alkyl group;
R ¹⁰ is —NR ⁷ R ⁸ or a heterocyclyl group;
R ¹¹ is a di-lower alkylamino group or a cyclic amino group;
A ¹ is a bond or a C _1-6 alkylene group;
A ³ is a C _1-6 alkylene group;
A ⁴ and A ⁵ are each independently a C _2-4 alkylene group] or a pharmacologically acceptable salt thereof. The group consisting of:
2,6-dimethylphenyl- {5- [4- (2-morpholin-4-ylethylamino) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine;
{5- [4- (2-dimethylaminoethoxy) phenyl] imidazo [1,5-a] pyrazin-8-yl} -2,6-dimethylphenylamine;
2,6-dimethylphenyl- {5- [4- (2-pyrrolidin-1-ylethoxy) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine;
2,6-dimethylphenyl- {5- [4- (1-methylpiperidin-3-ylmethoxy) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine;
2,6-dimethylphenyl- {5- [3- (1-methylpiperidin-3-ylmethoxy) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine;
N- (2-dimethylaminoethyl) -4- [8- (2,6-dimethylphenylamino) imidazo [1,5-a] pyrazin-5-yl] benzamide;
2,6-dimethylphenyl- {5- [4- (4-methylpiperazin-1-ylmethyl) phenyl] imidazo [1,5-a] pyrazin-8-yl} amine;
[5- (4-dimethylaminomethylphenyl) imidazo [1,5-a] pyrazin-8-yl)]-2,6-dimethylphenylamine;
2,6-dimethylphenyl- {5- [5- (4-methylpiperazin-1-ylmethyl) thiophen-2-yl] imidazo [1,5-a] pyrazin-8-yl} amine dihydrochloride;
2,6-Dimethylphenyl- [5- (5-pyrrolidin-1-ylmethylthiophene-2
-Yl) imidazo [1,5-a] pyrazin-8-yl] amine hydrochloride;
2-chloro-6-methylphenyl- [6- (2-methoxyphenyl) imidazo [1,5-a] pyrazin-8-yl] amine; and 4- [8- (2-chloro-6-methylphenylamino) ) Imidazo [1,5-a] pyrazin-6-yl] -N- (2-dimethylaminoethyl) benzamide,
Or a pharmacologically acceptable salt thereof. The pharmaceutical composition which contains the compound as described in any one of Claims 1-8, or its pharmacologically acceptable salt as an active ingredient. A therapeutic or prophylactic agent for a protein tyrosine kinase-related disease comprising the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof as an active ingredient. The therapeutic or prophylactic agent according to claim 10, wherein the protein tyrosine kinase-related disease is cancer. The therapeutic or prophylactic agent according to claim 10, wherein the protein tyrosine kinase-related disease is osteoporosis, Paget's disease, hypercalcemia, or osteoarthritis. The therapeutic or prophylactic agent according to claim 10, wherein the protein tyrosine kinase-related disease is Parkinson's disease, epilepsy, cerebral edema, acute cerebral infarction or cerebral vasospasm. The therapeutic or prophylactic agent according to claim 10, wherein the protein tyrosine kinase-related disease is a T cell-related disease. The therapeutic or prophylactic agent according to claim 14, wherein the T cell-related disease is an autoimmune disease, graft-versus-host disease, or rejection due to organ transplantation. The therapeutic or prophylactic agent according to claim 10, wherein the protein tyrosine kinase is an Src family kinase. The therapeutic or prophylactic agent according to claim 10, wherein the protein tyrosine kinase is Src. The therapeutic or prophylactic agent according to claim 10, wherein the protein tyrosine kinase is Lck. A compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt thereof, a bone disease agent other than an Src family kinase inhibitor, an antiparkinsonian agent, an antiepileptic agent, an acute phase cerebral infarction A pharmaceutical comprising a combination of at least one selected from a therapeutic agent, a therapeutic agent for cerebral vasospasm and a therapeutic agent for T cell-related diseases.