JP2011136925A - Nitrogen-containing bicyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound effective for a therapeutic agent or a prophylactic agent of rejection reaction at organ transplantation, autoimmune disease or the like. <P>SOLUTION: There is provided a compound represented by formula (I) or a salt thereof. [In the formula, X<SP>1</SP>is CR<SP>7</SP>or nitrogen; X<SP>2</SP>is CH or nitrogen; X<SP>3</SP>and X<SP>4</SP>are a group bonded to each other: -X<SP>3</SP>----X<SP>4</SP>- (wherein, the group is -CONR<SP>8</SP>-, -C(R<SP>9</SP>)=N- or the like); R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>, R<SP>4</SP>and R<SP>7</SP>are each independently hydrogen, halogen, 1-6C alkyl or the like; R<SP>5</SP>is hydrogen or -NHR<SP>10</SP>; R<SP>6</SP>is hydrogen, 1-6C alkyl or R<SP>10'</SP>; R<SP>8</SP>is hydrogen, 1-6C alkyl which may be substituted, or saturated aliphatic heterocycle; R<SP>9</SP>is hydrogen, 1-6C alkyl, 1-6C alkoxy or the like; R<SP>10</SP>and R<SP>10'</SP>are each 3-8C cycloalkyl, aryl-1-6C alkyl or the like]. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition, particularly a nitrogen-containing bicyclic compound useful as a therapeutic agent for autoimmune diseases.

Cytokines are factors that play an important role in various physiological functions such as differentiation and proliferation of immune system cells. Cytokines transmit signals into cells through their respective receptors, and Janus kinase (JAK), which is a non-receptor type protein kinase, is involved in this signal transduction process. When the cytokine binds to the receptor, JAK associates with the receptor and is activated, and subsequently phosphorylates STAT, which is a transcription factor, to activate STAT. Activated STATs translocate from the cytoplasm to the nucleus, bind to specific DNA sites, and control gene transcription. The JAK / STAT signal transduction system has been shown to be involved not only in normal immune responses but also in many abnormal immune responses such as autoimmune diseases, allergies and asthma, and malignant tumors such as leukemia and lymphoma. Therefore, it has been suggested that inhibiting JAK, that is, inhibiting the JAK / STAT signal transduction pathway is a therapeutic method in the above diseases (for example, Oncogene, 19 , 2645 (2000)).

  To date, four JAK families, JAK1, JAK2, JAK3, and TYK2, have been reported. JAK1, JAK2, and TYK2 are widely expressed, whereas JAK3 is mainly expressed in blood cells. JAK3 also associates with a γ chain commonly used as a receptor for interleukin (hereinafter abbreviated as IL-2) -2, IL-4, IL-7, IL-9, IL-15, and IL-21. Thus, since it is involved in signal transduction of these cytokines, a role in lymphocyte activation is suggested.

On the other hand, the regulation of immune system function is an important approach in the prevention and treatment of rejection during organ transplantation and the treatment of autoimmune diseases such as rheumatoid arthritis and psoriasis. JAK3 knockout mice show immunodeficiency symptoms lacking T cells, B cells, and natural killer cells, suggesting that JAK3 is involved not only in the maturation of B lymphocytes and T lymphocytes, but also in the maintenance of T lymphocyte functions. (For example, Science, 270 , 794 (1995)). In patients with X-linked severe combined immunodeficiency, a gene abnormality of the γ chain associated with JAK3 is observed, which is suggested to be caused by a defect in a signal transduction pathway via JAK3 (for example, Science, 270 , 797 (1995)). From the above, the control of immune function by inhibiting JAK3 is expected to be useful for the treatment of T cell proliferative diseases such as rejection at the time of organ transplantation and autoimmune diseases (for example, Trends in Pharmacological Sciences). , 25 , 558 (2004)).

Furthermore, the proliferation and survival of mouse mast cells induced by IL-4 and IL-9 depend on the JAK3 and γ chain signaling pathways (eg, Blood, 96 , 2172 (2000)), adult T cell leukemia In lymphomas, it has been reported that activation of the JAK / STAT signaling system is involved in leukemia cell replication (eg, Proc. Natl. Acad. Sci. USA, 94 , 13897 (1997)). It has been suggested that inhibition is also effective in allergic diseases and malignant tumors.
To date, a plurality of compounds having JAK3 inhibitory action have been reported. For example, Patent Document 1 describes a purine derivative represented by the following general formula.

(Wherein Q ₁ and Q ₂ are the same or different and are a group selected from CX ₁ , CX ₂ and nitrogen;
Q ₃ is N or CH,
X ₁ and X ₂ are the same or different and are groups selected from hydrogen, cyano, halo and the like,
V ₁ and V ₂ are the same or different and are groups selected from CH and N;
R ₁ is a group selected from hydrogen and methyl;
y is an integer selected from 0 or 1, 2, 3;
R ₂ and R ₃ are the same or different and are groups selected from the group consisting of hydrogen and (C _1-6 ) alkyl (CR ₂ R ₃ ),
R ₄ is a group selected from alkyl, heterocycle, aryl and the like. )

  The compound has a different structure of a bicyclic heteroaryl bonded to the 2-position of the purine ring, and a structure in which two types of bicyclic heteroaryl are bonded at a carbon atom-nitrogen atom has the following formula: It is different from the compound of the present invention represented by (I).

  Non-Patent Document 1 describes that a pyrrolopyrimidine derivative has JAK3 inhibitory activity, and Patent Document 2 and Non-Patent Document 2 describe that a pyrimidine derivative has JAK3 inhibitory activity. However, none of the documents discloses a compound of the present invention having a structural feature represented by the following formula (I).

  Patent Document 3 describes a compound having an imidazopyridine skeleton represented by the following general formula, which has glycogen synthase kinase-3 inhibitory activity.

Wherein X is C _0-6 alkyl-UC _0-6 alkyl, (C _2-6 alkenyl) _0-1 -U- (C _2-6 alkenyl) _0-1, etc. , U is CO or C (OR ⁵ ) R ⁶ ,
Ring A is imidazo [1,2a] pyrid-3-yl or pyrazolo [2,3a] pyrid-3-yl;
Ring B is a 5- or 6-membered heteroaromatic ring containing a heteroatom selected from N, O and S;
Ring C is a phenyl ring or a 5 or 6 membered heteroaromatic ring containing a heteroatom selected from N, O and S;
Ring D is a phenyl ring or a 5- or 6-membered heteroaromatic ring containing a heteroatom selected from N, O and S, and the like.
n is 1, 2 or 3;
R ¹ is hydrogen, halo, nitro, cyano, hydroxy, etc.
R ² , R ³ and R ⁴ are attached to the ring carbon and are independently hydrogen, halo, nitro, etc.
R ⁵ is hydrogen, fluoromethyl, alkyl or the like,
R ⁶ is hydrogen, alkyl, alkenyl or the like,
m, p and q are 1, 2, 3, 4 or 5. )

  The compound has a structure in which a ring C is directly connected to a 5- or 6-membered heteroaromatic ring of B via NH, and additionally has a ring D via X, which is represented by the following formula (I). Different from the compounds of the invention.

International Publication No. 2006/108103 Pamphlet International Publication No. 2007/098507 Pamphlet International Publication No. 2002/065979 Pamphlet

Bioorg. Med. Chem. Lett., 17, 1250 (2007) Bioorg. Med. Chem. Lett., 16,5633 (2006)

  An object of the present invention is to provide a compound effective as an agent for treating, improving, or preventing various immune diseases such as rejection in organ transplantation and autoimmune diseases.

As a result of intensive studies on compounds having JAK inhibitory activity, particularly JAK3 inhibitory activity, the present inventors have found that a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof is indicated as a pharmaceutical. The present invention was completed by discovering that it is a possible immunosuppressant, therapeutic or preventive for autoimmune diseases.
That is, the present invention relates to the following.

  [Item 1] The following formula (I):

[Where:
X ¹ represents CR ⁷ or a nitrogen atom,
X ² represents CH or a nitrogen atom,
X ³ and X ⁴ are groups bonded to each other: —X ³ ---- X ⁴ — (wherein the group is —CONR ⁸ —, —CSNR ⁸ —, —C (R ⁹ ) ═N— or — Represents CH = CH-) or
Or X ³ represents a hydrogen atom, and X ⁴ represents a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxycarbonyl, carboxyl, cyano, —NR ¹¹ R ¹² , —CONR ¹¹ R ¹² or —NHCO. It represents a -R ^13,
R ¹ , R ² , R ³ , R ⁴ and R ⁷ are each independently a C _1-6 alkyl which may be substituted with a hydrogen atom, a halogen atom or a fluorine atom, or a fluorine atom. _Represents good C _1-6 alkoxy, C _1-6 alkoxycarbonyl, saturated aliphatic heterocycle, nitro or cyano,
R ⁵ represents a hydrogen atom or —NHR ¹⁰ ;
R ⁶ represents a hydrogen atom, C _1-6 alkyl or R ^{10 ′} ,
R ⁸ is a hydrogen atom; fluorine atom, hydroxyl group, cyano, C _1-6 alkoxycarbonyl, carboxyl, heteroaryl, C _1-6 alkoxy, —NR ¹¹ R ¹² , —CONR ¹¹ R ¹² , saturated aliphatic heterocyclic ring , —NR ¹¹ —saturated aliphatic heterocycle, —O—saturated aliphatic heterocycle, —CO—saturated aliphatic heterocycle, C _1-6 alkanoylamino, aryl, —S (O) _n —C _{1 -6} alkyl, substituted by -SO ₂ NH-C _1-6 alkyl, -NHSO ₂ -C _1-6 alkyl and C _3-8 same or different 1 to 3 groups selected from the group consisting of cycloalkyl An optionally substituted C _1-6 alkyl (wherein the heteroaryl and the group containing a saturated aliphatic heterocyclic ring are a hydroxyl group, a halogen atom, C _1-6 alkoxy, or a C ₁ optionally substituted with fluorine. _-6 alkyl, -CO-C _1-6 alkyl, C _1-6 arco Optionally substituted with 1 to 3 identical or different groups selected from the group consisting of xyloxycarbonyl, —CONR ¹¹ R ¹² , carboxyl and cyano, the aryl is a hydroxyl group, a halogen atom, a C _1-6 alkoxy; , C _1-6 alkyl optionally substituted with fluorine, C _1-6 alkoxycarbonyl, —CONR ¹¹ R ¹² , carboxyl, cyano, and the same or different 1 to Represents a saturated aliphatic heterocyclic ring that may be substituted with C _1-6 alkyl, which may be substituted with three groups;
R ⁹ is a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy, aryl, heteroaryl, —S (O) _n —C _1-6 alkyl, —NHCO—C _1-6 alkyl, or —NR ¹¹ R ¹² represents
R ¹⁰ and R ^{10 ′} are each independently C _3-10 cycloalkyl, saturated aliphatic heterocycle, aryl, heteroaryl, C _3-8 cycloalkyl-C _1-6 alkyl, aryl-C _1-6. Alkyl or heteroaryl-C _1-6 alkyl, wherein each of R ¹⁰ and R ^{10 ′} is a hydroxyl group; a halogen atom; a cyano; a cyano, a hydroxyl group, a fluorine atom, a C _1-6 alkoxycarbonyl, a carboxyl, -CONR ¹¹ R ¹² and C _1-6 identical are selected from the group consisting of alkoxy or different one to three optionally substituted with C _1-6 alkyl; cyano, hydroxyl, fluorine atom, C _{1- 6} alkoxycarbonyl, carboxyl, -CONR ¹¹ R ¹² and C _1-6 same or different one to three C _1-6 alkoxy optionally substituted by groups selected from the group consisting of alkoxy; C _1-6 Alkoxycal Alkylsulfonyl; carboxyl; -S (O) _n -C _1-6 alkyl; -CO-R ¹³ and -CONR ¹¹ be substituted by the same or different 1 to 3 groups selected from the group consisting of R ¹² Often,
R ¹¹ represents a hydrogen atom or C _1-6 alkyl,
R ¹² and R ¹³ are each independently a hydrogen atom or C _1-6 alkyl (wherein the alkyl is a hydroxyl group, cyano, aryl, saturated aliphatic heterocyclic ring, amino, C _1-6 alkylamino and Di (C _1-6 alkyl) amino may be substituted with a group selected from the group consisting of:
n represents 0, 1 or 2;
In the above definition, when X ³ is a hydrogen atom or R ⁵ is —NHR ¹⁰ , X ² is a nitrogen atom]
Or a pharmaceutically acceptable salt thereof.

[Item 2] R ⁵ is a hydrogen atom and R ⁶ is R ^{10 ′} , or R ⁵ is —NHR ¹⁰ , and R ⁶ is a hydrogen atom or C _1-6 alkyl.
Item 12. The compound according to Item 1 or a pharmaceutically acceptable salt thereof.

[Claim 3] A group in which X ³ and X ⁴ are bonded to each other: —X ³ ---- X ⁴ — (wherein the group is —CONR ⁸ —, —CSNR ⁸ —, —C (R ⁹ ) = N- or -CH = CH-)
Or X ³ is a hydrogen atom, and X ⁴ is a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxycarbonyl, carboxyl, cyano, —NR ¹¹ R ¹² , —CONR ¹¹ R ¹² or —NHCO -R ¹³ and R ¹⁰ and R ^{10 '} are each independently C _3-10 cycloalkyl, saturated aliphatic heterocycle, heteroaryl-C _1-6 alkyl, C _3-8 cycloalkyl-C _{1. -6} alkyl or aryl-C _1-6 alkyl, wherein each group of R ¹⁰ and R ^{10 ′} is a hydroxyl group; a halogen atom; a cyano; a cyano, a hydroxyl group, a fluorine atom, a C _1-6 alkoxycarbonyl, carboxyl, -CONR ¹¹ R ¹² and C _1-6 same or different one to three optionally substituted with C _1-6 alkyl is selected from the group consisting of alkoxy, cyano, hydroxyl, fluorine atom, C _1-6 alkoxycarbonyl, potassium C _1-6 alkoxy optionally substituted with 1 to 3 identical or different groups selected from the group consisting of ruxoxyl, —CONR ¹¹ R ¹² and C _1-6 alkoxy; C _1-6 alkoxycarbonyl; carboxyl -S (O) _n -C _1-6 alkyl; optionally substituted by 1 to 3 identical or different groups selected from the group consisting of -CO-R ¹³ and -CONR ¹¹ R ¹² ;
Item 3. The compound according to Item 1 or Item 2, or a pharmaceutically acceptable salt thereof.

[Claim 4] R ¹⁰ and R ^{10 ′} are each independently C _3-10 cycloalkyl, saturated aliphatic heterocycle, C _3-8 cycloalkyl-C _1-6 alkyl, heteroaryl-C _1-6. Alkyl or aryl-C _1-6 alkyl, wherein each group of R ¹⁰ and R ^{10 ′} is the same or different selected from the group consisting of hydroxyl group; halogen atom; cyano; cyano, hydroxyl group and fluorine atom C _1-6 alkyl optionally substituted with 1 to 3 groups; and C optionally substituted with 1 to 3 identical or different groups selected from the group consisting of cyano, hydroxyl group and fluorine atom Optionally substituted with 1 to 3 identical or different groups selected from the group consisting of _1-6 alkoxy;
Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.

[Item 5] R ¹⁰ and R ^{10 ′} are each independently C _3-10 cycloalkyl, aryl, or aryl-C _1-6 alkyl, wherein each group of R ¹⁰ and R ^{10 ′} is , Hydroxyl group; halogen atom; cyano; cyano, hydroxyl group, fluorine atom, C _1-6 alkoxycarbonyl, carboxyl, —CONR ¹¹ R ¹² and C _1-6 alkoxy selected from the same or different 1 to 3 C _1-6 alkyl optionally substituted by a group; and the same selected from the group consisting of cyano, hydroxyl group, fluorine atom, C _1-6 alkoxycarbonyl, carboxyl, —CONR ¹¹ R ¹² and C _1-6 alkoxy Or optionally substituted with 1 to 3 identical or different groups selected from the group consisting of C _1-6 alkoxy optionally substituted with 1 to 3 different groups,
Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.

[Item 6] R ¹⁰ and R ^{10 ′} are each independently C _3-10 cycloalkyl or aryl-C _1-6 alkyl, wherein each group of R ¹⁰ and R ^{10 ′} is a hydroxyl group , a halogen atom, the same or different 1 to 3 groups selected from the group consisting of even a C _1-6 alkoxy substituted in C _1-6 alkyl and fluorine atoms substituted by a fluorine atom May be substituted,
Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.

[Claim 7] R ⁸ is a hydrogen atom; or fluorine atom, hydroxyl group, cyano, C _1-6 alkoxycarbonyl, carboxyl, heteroaryl, C _1-6 alkoxy, —NR ¹¹ R ¹² , —CONR ¹¹ R ¹² , saturated Aliphatic heterocycle, —NR ¹¹ -saturated aliphatic heterocycle, —O-saturated aliphatic heterocycle, —CO-saturated aliphatic heterocycle and C _3-8 cycloalkyl, wherein aryl and groups containing hetero ring to saturated aliphatic, a hydroxyl group, a halogen atom, C _1-6 alkoxy, -CO-C _1-6 alkyl, optionally substituted by fluorine C _1-6 alkyl, C _{1 -6} alkoxycarbonyl, -CONR ¹¹ R ^12, same or different 1 to 3 selected from the group consisting of may also) be substituted with same or different 1 to 3 groups selected from the group consisting of carboxyl and cyano Substituted with C _1-6 alkyl, which may be
Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof.

[Item 8] R ⁸ represents a hydrogen atom; or a hydroxyl group, cyano, C _1-6 alkoxycarbonyl, carboxyl, C _1-6 alkoxy, —NR ¹¹ R ¹² , —CONR ¹¹ R ¹² , a saturated aliphatic heterocyclic ring, and -CO-saturated aliphatic heterocycle, wherein the group containing the saturated aliphatic heterocycle is a hydroxyl group, C _1-6 alkoxy, -CO-C _1-6 alkyl, C _1-6 alkoxycarbonyl, Substituted with 1 to 3 identical or different groups selected from the group consisting of 1 to 3 identical or different groups selected from the group consisting of —CONR ¹¹ R ¹² and carboxyl; C _1-6 alkyl, which may be
Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof.

[Item 9] R ⁸ is the same or different selected from the group consisting of a hydrogen atom; or a hydroxyl group, C _1-6 alkoxycarbonyl, carboxyl, C _1-6 alkoxy, —NR ¹¹ R ¹² and —CONR ¹¹ R ^12. Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof, which is C _1-6 alkyl _optionally substituted with 1 to 2 groups.

[Item 10] A group in which X ³ and X ⁴ are bonded to each other: —X ³ ---- X ⁴ — (wherein the group is —CONR ⁸ —, —CSNR ⁸ —, —C (R ⁹ ) = N- or -CH = CH-).
Item 10. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.

[Item 11] X ³ is a hydrogen atom, and X ⁴ is a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxycarbonyl, carboxyl, or —CONR ¹¹ R ¹² .
Item 10. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.
[Item 12] X ³ is a hydrogen atom, and X ⁴ is a hydrogen atom, a halogen atom, C _1-6 alkyl or carboxyl.
Item 10. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.

[Item 13] X ³ and X ⁴ are a group bonded to each other: —X ³ ---- X ⁴ — (wherein the group is —CONR ⁸ — or —CSNR ⁸ —).
Item 10. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.

[Item 14] A group in which X ³ and X ⁴ are bonded to each other: —X ³ ---- X ⁴ — (wherein the group is —C (R ⁹ ) ═N— or —CH═CH—. )
Item 10. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.

[Item 15] X ² is CH.
Item 15. The compound according to any one of Items 1 to 14 or a pharmaceutically acceptable salt thereof.

[Item 16] X ² is a nitrogen atom.
Item 15. The compound according to any one of Items 1 to 14 or a pharmaceutically acceptable salt thereof.

[Section 17] X ¹ is CR ⁷ .
Item 17. The compound according to any one of Items 1 to 16 or a pharmaceutically acceptable salt thereof.

[Item 18] X ¹ is a nitrogen atom.
Item 17. The compound according to any one of Items 1 to 16 or a pharmaceutically acceptable salt thereof.

[Item 19] R ⁹ is a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy, —S (O) n—C _1-6 alkyl, or —NR ¹¹ R ¹² .
Item 19. The compound according to any one of Items 1 to 18 or a pharmaceutically acceptable salt thereof.

[Item 20] R ¹ , R ² , R ³ , R ⁴ and R ⁷ are each a hydrogen atom,
Item 20. The compound according to any one of Items 1 to 19 or a pharmaceutically acceptable salt thereof.

  [Item 21] A pharmaceutical composition comprising the compound according to any one of items 1 to 20 or a pharmaceutically acceptable salt thereof.

  [Item 22] A therapeutic or prophylactic agent for an autoimmune disease comprising the compound according to any one of Items 1 to 20 or a pharmaceutically acceptable salt thereof as an active ingredient.

  [Item 23] Treatment of rejection, autoimmune disease, allergic disease, malignant tumor, etc. in organ transplantation containing the compound according to any one of Items 1 to 20 or a pharmaceutically acceptable salt thereof as an active ingredient Drug or preventive drug.

  According to the present invention, it is possible to provide a nitrogen-containing bicyclic compound or a pharmaceutically acceptable salt thereof useful as a therapeutic or prophylactic agent for rejection in organ transplantation, autoimmune diseases, allergic diseases, malignant tumors and the like. it can.

  Since the compounds of the present invention may exist in the form of hydrates and / or solvates, these hydrates and / or solvates are also encompassed by the compounds of the present invention.

  In addition, the compounds of formula (I) may have one or more than one asymmetric carbon atom, and may cause geometric isomerism and axial chirality. May exist. In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention.

  The present invention is described in further detail below. Unless otherwise specified, the description of each group also applies when the group is a part of another group or a substituent.

The definitions of X ³ and X ⁴ in the compound (I) of the present invention are as follows.
The compound (I) in which X ³ and X ⁴ are a group bonded to each other: —CONR ⁸ — means a compound represented by the following formula (I-1).

The compound (I) in which X ³ and X ⁴ are a group bonded to each other: —CSNR ⁸ — means a compound represented by the following formula (I-2).

The compound (I) in which X ³ and X ⁴ are groups bonded to each other: —C (R ⁹ ) ═N— means a compound represented by the following formula (I-3).

Further, the compound (I) in which X ³ and X ⁴ are groups bonded to each other: —CH═CH 2 — means a compound represented by the following formula (I-4).

X ³ is a hydrogen atom, and X ⁴ is a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxycarbonyl, carboxyl, cyano, —NR ¹¹ R ¹² , —CONR ¹¹ R ¹² or — The compound (I) which is NHCO-R ¹³ and X ² is a nitrogen atom means a compound represented by the following formula (I-5).

“Alkyl” includes, for example, linear or branched alkyl. “C _1-6 alkyl” means a group having 1 to 6 carbon atoms. Specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.

“Cycloalkyl” includes, for example, monocyclic cycloalkyl or bridged carbocycle. For example, “C _3-8 cycloalkyl” or “C _3-10 cycloalkyl” means a saturated hydrocarbon having 3 to 8 or 3 to 10 carbon atoms, respectively. As specific examples, in the case of “C _3-8 cycloalkyl”, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like are in the case of “C _3-10 cycloalkyl”, In addition, nonyl, decanyl, adamantyl, norbornel and the like can be mentioned. In addition, the case where aryl is condensed to the cycloalkyl to form a bicyclic compound is also included in “cycloalkyl”. Specific examples thereof include 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl and the like. Further, the cycloalkyl in the present invention may contain one oxo form. Specific examples thereof include 4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl, 3-oxo-2,3-dihydro-1H-inden-1-yl and the like.

“Alkoxy” includes, for example, linear or branched alkoxy. “C _1-6 alkoxy” means linear or branched alkoxy having 1 to 6 carbon atoms. Specific examples thereof include methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 1-ethylpropoxy, hexyloxy, 1 -Methylpentyloxy, 2-methylpentyloxy, 1-ethylbutoxy and the like.

Examples of “alkanoylamino” include linear or branched alkanoylamino. “C _1-6 alkanoylamino” means an amino group to which a hydrogen atom or a carbonyl (total number of carbon atoms of 1 to 6) to which a linear or branched hydrocarbon is bonded is bonded. Specific examples include formylamino, acetylamino, propionylamino, butyrylamino and the like.

Examples of “alkoxycarbonyl” include linear or branched alkoxycarbonyl. “C _1-6 alkoxycarbonyl” means a group in which a carbonyl is bonded to a C _1-6 alkoxy to which a linear or branched hydrocarbon is bonded. Specific examples include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexaoxycarbonyl and the like.

  Specific examples of “aryl” include phenyl, 1-naphthyl, 2-naphthyl and the like.

  “Heteroaryl” includes a monocyclic or bicyclic 5- to 10-membered aromatic heterocyclic group containing 1 to 3 nitrogen atoms, oxygen atoms and / or sulfur atoms. Specifically, 1-3 of pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, triazolyl, tetrazolyl, etc. Monocyclic 5- to 7-membered aromatic heterocycles containing nitrogen, oxygen and / or sulfur atoms, indolyl, indazolyl, chromenyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benz 2- to 10-membered bicyclic ring containing 1 to 3 nitrogen atoms, oxygen atoms and / or sulfur atoms such as isoxazolyl, benzisothiazolyl, benzotriazolyl or benzimidazolyl They include aromatic heterocyclic. Preferred heteroaryls include pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, quinolyl, isoquinolyl.

As the “saturated aliphatic heterocycle”, for example, a monocyclic 5 to 8 membered saturated aliphatic heterocycle containing 1 to 3 nitrogen atoms, oxygen atoms and / or sulfur atoms, and 7 to 9 membered bicyclosaturation Bicyclic heterocycles in which an aryl or heteroaryl is condensed to an aliphatic heterocycle and a monocyclic saturated aliphatic heterocycle are exemplified.
Specific examples of the monocyclic 5- to 8-membered saturated aliphatic heterocycle include monocyclic compounds containing 1 to 3 nitrogen atoms, oxygen atoms and / or sulfur atoms such as tetrahydrofuran, pyrrolidine, pyrazolidine, thiazolidine, or oxazolidine. Monocyclic 6-membered saturated heterocycles containing 1 to 3 nitrogen atoms, oxygen atoms and / or sulfur atoms, such as 5-membered saturated heterocycles of ring, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran or dioxane And a monocyclic 7-membered saturated heterocycle containing 1 to 3 nitrogen atoms, oxygen atoms and / or sulfur atoms, such as a ring, azepane or oxepane.
Specific examples of the 7 to 9-membered bicyclo saturated aliphatic heterocycle include, for example, 7-azabicyclo [2.2.1] heptane, 3-azabicyclo [3.2.1] octane, and 3-azabicyclo [3.2. 2] 7-9 membered bicyclo saturated heterocycles containing 1 to 3 nitrogen atoms, oxygen atoms and / or sulfur atoms such as nonane or 8-oxabicyclo [3.2.1] octane.
Specific examples of the bicyclic heterocycle in which aryl or heteroaryl is condensed to a monocyclic saturated aliphatic heterocycle include, for example, 2,3-dihydrobenzofuran, indoline, chroman, 2,3-dihydro-1 , 4-benzodioxin, 3,4-dihydro-2H-1,4-benzoxazine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4 -Tetrahydroquinoxaline, 2,3,4,5-tetrahydro-1H-1benzazepine, 2,3,4,5-tetrahydro-1-benzoxepin, 6,7-dihydro-5H-cyclopenta [b] pyridine, 6,7 -Dihydro-5H-cyclopenta [c] pyridine, 4,5,6,7-tetrahydrobenzofuran, 5,6,7,8-tetrahydroquinoline, 5, 7,8 tetrahydroisoquinoline, 5,6,7,8-tetrahydroquinoxaline and the like.
Preferred saturated aliphatic heterocycles include tetrahydropyran, pyrrolidine, piperidine, piperazine, morpholine, oxepane, 2,3-dihydrobenzofuran, chroman, 6,7-dihydro-5H-cyclopenta [b] pyridine, 4,5, Examples include 6,7-tetrahydrobenzofuran, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroquinoxaline and the like.

“C _3-8 cycloalkyl-C _1-6 alkyl” means a group in which one hydrogen atom of C _1-6 alkyl is replaced by C _3-8 cycloalkyl. Specific examples thereof include cyclopropylmethyl, cyclobutylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclopropylpropyl, 2-cyclopropylpropyl, 1-cyclobutylethyl, 2-cyclobutylethyl, Examples include cyclopentylmethyl and cyclohexylmethyl.

Similar to “C _3-8 cycloalkyl-C _1-6 alkyl”, “aryl-C _1-6 alkyl” or “heteroaryl-C _1-6 alkyl” is one of C _1-6 alkyl. In which the hydrogen atom is replaced by the above aryl or heteroaryl. In addition, “—S (O) _n —C _1-6 alkyl”, “—SO ₂ NH—C _1-6 alkyl” or “—NHSO ₂ —C _1-6 alkyl” means that C _1-6 alkyl is each Each group bonded through a spacer is meant.

  “Halogen atom” includes fluorine atom, chlorine atom, bromine atom or iodine atom.

Preferred groups of X ^{1 to} X ⁴ , R ^{1 to} R ¹³ and n in the compound of the present invention represented by the formula (I) are as follows.

X ¹ may be CR ⁷ or a nitrogen atom, preferably CR ⁷ . X ² includes CH or a nitrogen atom, preferably a nitrogen atom.

If X ³ and X ⁴ are bonded to each other, -X ³ ---- X ⁴ - ^{a, -CONR 8 -, - CSNR 8} -, - C (R 9) = N- or -CH = CH- Although the like, ^{preferably, -CONR 8 -, - CSNR 8} - or -C (R ⁹⁾ = a N-. More preferred is —CONR ⁸ — or —CSNR ⁸ —, and particularly preferred is —CONR ⁸ —. When X ³ and X ⁴ are not bonded to each other and X ³ represents a hydrogen atom, X ⁴ represents a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxycarbonyl, carboxyl, cyano, — NR ¹¹ R ¹² , —CONR ¹¹ R ¹² or —NHCO—R ¹³ may be mentioned, and hydrogen atom, halogen atom, C _1-6 alkyl, carboxyl or —CONR ¹¹ R ¹² is preferable. More preferred is a hydrogen atom, C _1-6 alkyl or carboxyl, and particularly preferred is a hydrogen atom, methyl or carboxyl.

R ¹ , R ² , R ³ and R ⁴ are each hydrogen atom, halogen atom, C _1-6 alkyl optionally substituted with fluorine atom, C _1-6 alkoxy optionally substituted with fluorine atom, C Examples thereof include _1-6 alkoxycarbonyl, saturated aliphatic heterocyclic ring, nitro and cyano, preferably hydrogen atom, halogen atom and cyano. More preferably, it is a hydrogen atom.

The R ^5, include a hydrogen atom or -NHR ^10, as the R ^6, a hydrogen atom, C _1-6 alkyl or R ^{10 'is} the like, R ⁶ is R ^10' when the, R ⁵ is A hydrogen atom is preferred, and when R ⁵ is —NHR ¹⁰ , R ⁶ is preferably a hydrogen atom or C _1-6 alkyl. When R ⁵ is —NHR ¹⁰ , a more preferred group of R ⁶ is a hydrogen atom, methyl or ethyl, and a more preferred group is a hydrogen atom.

The R ^7, each represent a hydrogen atom, a halogen atom, a C _1-6 alkyl optionally substituted with fluorine atoms, which may be substituted by a fluorine atom C _1-6 alkoxy, C _1-6 alkoxycarbonyl, saturated aliphatic Heterocycle, nitro or cyano may be mentioned, and hydrogen atom, halogen atom, C _1-6 alkyl or cyano is preferred. More preferred is a hydrogen atom, a halogen atom or cyano, and particularly preferred is a hydrogen atom, a fluorine atom, a chlorine atom or cyano.

R ⁸ is hydrogen atom; fluorine atom, hydroxyl group, cyano, C _1-6 alkoxycarbonyl, carboxyl, heteroaryl, C _1-6 alkoxy, —NR ¹¹ R ¹² , —CONR ¹¹ R ¹² , saturated aliphatic hetero Ring, —NR ¹¹ —saturated aliphatic heterocycle, —O—saturated aliphatic heterocycle, —CO—saturated aliphatic heterocycle, C _1-6 alkanoylamino, aryl, —S (O) _n —C _1-6 alkyl, substituted with 1 to 3 identical or different groups selected from the group consisting of —SO ₂ NH—C _1-6 alkyl, —NHSO ₂ —C _1-6 alkyl and C _3-8 cycloalkyl An optionally substituted C _1-6 alkyl (wherein the heteroaryl and the group containing a saturated aliphatic heterocycle are a hydroxyl group, a halogen atom, a C _1-6 alkoxy, a C optionally substituted with fluorine) _1-6 alkyl, -CO-C _1-6 alkyl, C _1-6 The aryl may be substituted with the same or different 1 to 3 groups selected from the group consisting of alkoxycarbonyl, —CONR ¹¹ R ¹² , carboxyl and cyano, and the aryl is a hydroxyl group, a halogen atom, a C _1-6 alkoxy , C _1-6 alkyl optionally substituted with fluorine, C _1-6 alkoxycarbonyl, —CONR ¹¹ R ¹² , carboxyl, cyano, and the same or different 1 to 3 may be substituted with 3 groups); or saturated aliphatic heterocycles _optionally substituted with C _1-6 alkyl. Preferably, hydrogen atom; fluorine atom, hydroxyl group, cyano, alkoxycarbonyl, carboxyl, heteroaryl, C _1-6 alkoxy, —NR ¹¹ R ¹² , —CONR ¹¹ R ¹² , saturated aliphatic heterocycle, —CO—saturated C _1-6 alkyl optionally substituted by 1 to 3 identical or different groups selected from the group consisting of aliphatic heterocycles and C _3-8 cycloalkyl. More preferably, the same or different 1-3 selected from the group consisting of a hydrogen atom; a hydroxyl group, cyano, C _1-6 alkoxy, —NR ¹¹ R ¹² , —CONR ¹¹ R ¹² and a saturated aliphatic heterocycle. C _1-6 alkyl _optionally substituted with a group. Particularly preferred is a hydrogen atom; methyl or ethyl which may be substituted with 1 to 3 identical or different groups selected from the group consisting of a hydroxyl group, C _1-6 alkoxy and —NR ¹¹ R ¹² .

R ⁹ is a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy, aryl, heteroaryl, —S (O) _n —C _1-6 alkyl, —NHCO—C _1-6 alkyl, or —NR ^11. R ¹² may be mentioned, and preferably a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy, —S (O) _n —C _1-6 alkyl, or —NR ¹¹ R ¹² . More preferred is a hydrogen atom, C _1-6 alkyl, —S—C _1-6 alkyl or —NHR ¹¹ , and particularly preferred is a hydrogen atom, methyl or ethyl.

R ¹⁰ and R ^{10 ′} are each C _3-10 cycloalkyl, saturated aliphatic heterocycle, aryl, heteroaryl, C _3-8 cycloalkyl-C _1-6 alkyl, aryl-C _1-6 alkyl or hetero Aryl-C _1-6 alkyl is mentioned. Preferred examples include C _3-8 cycloalkyl, saturated aliphatic heterocycle, C _3-8 cycloalkyl-C _1-6 alkyl, heteroaryl-C _1-6 alkyl or aryl-C _1-6 alkyl, and more. Preferably, C _3-8 cycloalkyl, saturated aliphatic heterocycle, heteroaryl-C _1-6 alkyl or aryl-C _1-6 alkyl is mentioned, more preferably C _3-8 cycloalkyl, saturated aliphatic. Heterocycle or aryl-C _1-6 alkyl is mentioned. Particularly preferred is C _3-8 cycloalkyl or aryl-C _1-6 alkyl.

Examples of the substituent for each of R ¹⁰ and R ^{10 ′} include a hydroxyl group, a halogen atom, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxycarbonyl, carboxyl, —S (O) _n —. And C _1-6 alkyl, —CO—R ¹³ or —CONR ¹¹ R ¹² . Preferably, a hydroxyl group, a halogen atom, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxycarbonyl or —CONR ¹¹ R ¹² is mentioned, and more preferably, a hydroxyl group, a halogen atom, cyano, C _Examples include _1-6 alkyl or C _1-6 alkoxy. More preferred are a hydroxyl group, a halogen atom, C _1-6 alkyl or C _1-6 alkoxy, and particularly preferred are a hydroxyl group, a fluorine atom, a chlorine atom, methyl, ethyl or methoxy.

R ¹¹ includes a hydrogen atom or C _1-6 alkyl, preferably a hydrogen atom, methyl or ethyl.

R ¹² and R ¹³ include a hydrogen atom or C _1-6 alkyl, preferably a hydrogen atom, methyl or ethyl.

  As n, 0, 1 or 2 is mentioned, Preferably 0 or 2 is mentioned, Especially preferably, 0 is mentioned.

Preferable specific examples of X ^{1 to} X ⁴ , R ^{1 to} R ¹³ and n in the compound of the formula (I) include the following. X ¹ is preferably CR ⁷ ; X ³ and X ⁴ are bonded to each other, and —X ³ ---- X ⁴ — is a structure of —CONR ⁸ — or —CSNR ⁸ — or not bonded to each other. R ³ , X ³ is hydrogen, and X ⁴ is hydrogen, methyl, or carboxyl. The R ¹ , R ² , R ^3, and R ⁴ are preferably hydrogen atoms; R ⁵ is preferably a hydrogen atom; R ⁶ Is preferably R ^{10 ′} ; R ⁷ is preferably a hydrogen atom, a fluorine atom, a chlorine atom or cyano; R ⁸ is a hydrogen atom; or a hydroxyl group, C _1-6 alkoxy and —NR ¹¹ R ¹² Preferred is methyl or ethyl which may be substituted with the same or different 1 to 3 groups selected from the group consisting of: R ⁹ is preferably a hydrogen atom, methyl or ethyl; R ¹⁰ and R ^{10 ′} are , C _3-8 cycloalkyl or ants Le -C _1-6 alkyl is preferred, as a substituent for the group R ¹⁰ and R ^{10 ',} a hydroxyl group, a fluorine atom, a chlorine atom, methyl, ethyl or methoxy is preferred; as R ¹¹ represents a hydrogen atom, methyl Or, ethyl is preferred; R ¹² and R ¹³ are preferably a hydrogen atom, methyl or ethyl. Each of the above compound groups limited by one or a combination of any of these exemplifications is also an embodiment of a preferred compound of formula (I).

  A pharmaceutically acceptable salt of a compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I) when it has sufficient basicity or acidity to form a salt. It means an acceptable salt, for example, an acid addition salt with an inorganic acid or an organic acid. Examples of the salt with an inorganic acid include hydrochloride, hydrobromide, nitrate, sulfate, phosphate, and the like. Examples of salts with organic acids include formate, acetate, trifluoroacetate, propionate, lactate, tartrate, oxalate, fumarate, maleate, citrate, malonic acid Examples thereof include salts, methanesulfonate, and benzenesulfonate. Moreover, when acidic functional groups, such as a carboxyl group, exist in the compound represented by Formula (I), it can also be set as a salt with a base. Examples of the salt with a base include a salt with an organic base such as arginine, lysine or triethylammonium, a salt with an inorganic base such as an alkali metal (sodium or potassium) or an alkaline earth metal (such as calcium or barium), or An ammonium salt etc. are mentioned. The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may take the form of a solvate such as a hydrate thereof.

Note that the following abbreviations may be used to simplify the description in this specification. p-: para-, t-: tert-, s-: sec-, THF: tetrahydrofuran, DMF: N, N- dimethylformamide, DME: ethylene glycol dimethyl ether, DMSO: dimethylsulfoxide, CDCl _3: deuterated chloroform, DMSO- d ₆ : heavy dimethyl sulfoxide, OMs: methanesulfonyloxy, OTs: toluenesulfonyloxy, OTf: trifluoromethanesulfonyloxy

[Production Method 1]
In the formula (I), the compound [compound of the following formula (I-1a)] in which X ³ and X ⁴ are groups bonded to each other: —CONR ⁸ — can be produced, for example, according to the following method.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , X ¹ and X ² have the same meanings as in item 1, and A ¹ , A ^{1 ′} and A ^{1 ″} are And each independently a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, OMs, OTs or OTf, and M is a metal used in a cross-coupling reaction of tin, boron or zinc.)

[Step 1]
Compound (1-3) is produced by reacting compound (1-1) and compound (1-2) in the presence or absence of a base. The amount of compound (1-2) to be used is usually selected from the range of 1 equivalent to excess with respect to compound (1-1). Examples of the solvent include ether solvents (THF, diethyl ether, DME, 1,4-dioxane, etc.), aprotic polar solvents (DMF, N, N-dimethylacetamide, DMSO, acetonitrile, etc.), water, alcohols, and the like. A solvent (methanol, ethanol, etc.) or a mixed solvent thereof can be used. Examples of the base include alkali metal carbonates (cesium carbonate, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.), alkali metal hydrides (sodium hydride, potassium hydride, etc.), alkali metal hydroxides (hydroxide) Potassium, sodium hydroxide, etc.), organic bases (N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4. 3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, etc.), preferably potassium carbonate, diisopropylethylamine, and triethylamine. The amount of the base used is usually selected from the range of 1 to 5 equivalents relative to compound (1-1). The reaction temperature can usually be selected from the range of -78 to 150 ° C, preferably in the range of -78 to 50 ° C.

[Step 2]
Compound (1-5) is produced by reacting compound (1-3) with compound (1-4). The reaction can be carried out under normal coupling reaction conditions using a catalytic amount of a transition metal and a ligand in the presence or absence of a base. For example, when M is boron, normal Suzuki coupling conditions, when M is tin, normal Stille coupling conditions, and when M is zinc, normal Negishi coupling conditions can be mentioned (Handbook of Organopalladium Chemistry for Organic Synthesis, Negishi, A Wiley-Interscience Publication (2002), Angew. Chem. Int. Ed., 44 , 4442, (2005)). Specifically, as the transition metal catalyst, for example, palladium catalyst (palladium acetate, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium. (II) dichloride and the like) and nickel catalyst ([1,3-bis (diphenylphosphino) propane] dichloronickel and the like). A ligand may be used as necessary. Examples of the ligand include a phosphine ligand (triphenylphosphine, tri (t-butyl) phosphine, trifurylphosphine, etc.), a carbene ligand (1,3-bis (2,6-diisopropylphenyl) imidazole). 2-ylidene and the like). Examples of the base include alkali metal carbonates (cesium carbonate, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.), alkali metal hydroxides (potassium hydroxide, sodium hydroxide, etc.), alkali metal alkoxides (sodium ethoxide). , Sodium tert-butoxide, potassium tert-butoxide, etc.), organic base (N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5 -Diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine and the like). Further, for example, an additive such as an alkali metal fluoride (such as cesium fluoride) may be used. Examples of the solvent include ether solvents (THF, diethyl ether, DME, 1,4-dioxane, etc.), aprotic solvents (toluene, etc.), aprotic polar solvents (DMF, N, N-dimethylacetamide, DMSO). , Acetonitrile, etc.), water, alcohol solvents (methanol, ethanol, etc.), or a mixed solvent thereof. As reaction temperature, it can select from the range of 0-200 degreeC normally, Preferably it is performed in the range of 50-150 degreeC. You may utilize a microwave as needed.

[Step 3]
Compound (1-6) is produced by reducing the nitro group of compound (1-5). As a reduction method, a catalytic reduction method using a hydrogen source (hydrogen gas, ammonium formate, etc.) and a catalyst (palladium carbon, palladium hydroxide, platinum oxide, etc.), iron / acetic acid, aqueous titanium trichloride, tin (II) chloride, Examples thereof include a method using sodium hydrosulfite. Examples of the solvent include ether solvents (THF, etc.), aprotic polar solvents (acetonitrile, ethyl acetate, etc.), acids (acetic acid, etc.), water, alcohol solvents (methanol, ethanol, etc.), or a mixed solvent thereof. Is mentioned. As reaction temperature, it can select from the range of 0-150 degreeC normally.

[Step 4]
Compound (1-7) is produced by subjecting compound (1-6) to a carbonylation reaction in an inert solvent in the presence or absence of a base. As the carbonylation reagent, for example, carbonyldiimidazole, triphosgene, phosgene and the like are used. Examples of the inert solvent include ether solvents (THF, diethyl ether, DME, 1,4-dioxane, etc.), aprotic polar solvents (DMF, N, N-dimethylacetamide, DMSO, acetonitrile, etc.), ketones, and the like. (Acetone etc.), or these mixed solvents are mentioned. Examples of the base include organic bases (N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3. 0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine and the like. As reaction temperature, it can select normally from the range of -78-150 degreeC, Preferably it carries out in the range of 0-100 degreeC.

[Step 5]
Compound (I-1a) is produced by reacting compound (1-7) with compound (1-8) in the presence of a base in an inert solvent. The amount of compound (1-8) to be used is generally selected from the range of 1 equivalent to excess with respect to compound (1-7). Examples of the inert solvent include ether solvents (THF, diethyl ether, DME, 1,4-dioxane, etc.), aprotic polar solvents (DMF, N, N-dimethylacetamide, DMSO, acetonitrile, etc.), ketones, and the like. (Acetone etc.), or these mixed solvents are mentioned.
Examples of the base include alkali metal carbonates (cesium carbonate, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.), alkali metal hydrides (sodium hydride, potassium hydride, etc.), alkali metal hydroxides (hydroxide) Potassium, sodium hydroxide, etc.), alkali metal alkoxides (sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), organic bases (N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [ 5.4.0] Undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, etc. Preferably, potassium carbonate, water Sodium reduction, of potassium tert- butoxide, and triethylamine. The amount of the base used is usually selected from the range of 1 to 5 equivalents relative to compound (1-7). As reaction temperature, it can select normally from the range of -78-150 degreeC, Preferably it carries out in the range of 0-100 degreeC.

[Production Method 2]
In the formula (I), compounds in which X ³ and X ⁴ are bonded to each other: —CONR ⁸ —, R ⁵ is —NHR ¹⁰ , and X ² is a nitrogen atom [the following formula (I-1b) Can be produced, for example, according to the following method.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ¹⁰ and X ¹ are as defined in item 1, and A ¹ , A ^{1 ′} , A ^{1 ″} and M are the same as in Production Method 1. And A ² is a chlorine atom, a bromine atom or an iodine atom.)

[Step 1]
Compound (2-3) is produced by reacting compound (2-1) with compound (2-2) in the presence of a base in an inert solvent. The amount of compound (2-2) to be used is usually selected from the range of 1 equivalent to excess amount relative to compound (2-1). Examples of the inert solvent include ether solvents (THF, diethyl ether, DME, 1,4-dioxane, etc.), aprotic polar solvents (DMF, N, N-dimethylacetamide, DMSO, acetonitrile, etc.), ketones, and the like. (Acetone etc.), or these mixed solvents are mentioned. Examples of the base include alkali metal carbonates (cesium carbonate, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.), alkali metal hydrides (sodium hydride, potassium hydride, etc.), alkali metal hydroxides (hydroxide) Potassium, sodium hydroxide, etc.), alkali metal alkoxides (sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), organic bases (N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [ 5.4.0] Undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, etc. Preferably, potassium carbonate, water Sodium reduction, of potassium tert- butoxide, and triethylamine. The amount of base used is usually selected from the range of 1 to 5 equivalents relative to compound (2-1). As reaction temperature, it can select normally from the range of -78-150 degreeC, Preferably it carries out in the range of 0-100 degreeC. Although a regioisomer is also produced, the desired compound (2-3) is usually obtained as the main product.

[Step 2]
Compound (2-5) is produced by reacting compound (2-3) with compound (2-4) in the presence or absence of a base. The amount of compound (2-4) to be used is generally selected from the range of 1 equivalent to excess with respect to compound (2-3). Examples of the solvent include ether solvents (THF, diethyl ether, DME, 1,4-dioxane, etc.), aprotic polar solvents (DMF, N, N-dimethylacetamide, DMSO, acetonitrile, etc.), water, alcohols, and the like. A solvent (methanol, ethanol, etc.) or a mixed solvent thereof can be used. Examples of the base include alkali metal carbonates (cesium carbonate, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.), alkali metal hydrides (sodium hydride, potassium hydride, etc.), alkali metal hydroxides (hydroxide) Potassium, sodium hydroxide, etc.), organic bases (N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4. 3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, etc.), preferably potassium carbonate, diisopropylethylamine, and triethylamine. The amount of the base used is usually selected from the range of 1 equivalent to an excess amount relative to the compound (2-3). As reaction temperature, it can select from the range of 0-200 degreeC normally, Preferably it is performed in the range of 50-150 degreeC. If necessary, it may be performed using microwaves or under sealing conditions.

[Step 3]
Compound (2-6) is produced by reacting compound (2-5) with a halogenating agent in the presence of a base. Examples of the solvent include ether solvents (THF, diethyl ether, DME, 1,4-dioxane, etc.), chlorine solvents (chloroform, methylene chloride, etc.), or a mixed solvent thereof. Examples of the base include organic lithium (butyllithium, methyllithium, etc.), alkali metal acetate (sodium acetate, etc.), and alkali metal amide (lithium diisopropylamide, lithium amide, etc.). It is usually selected from the range of 1 to 20 equivalents relative to 2-5). Examples of the halogenating agent include bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and the like. The reaction temperature is usually selected from the range of -78 to 150 ° C, preferably in the range of -78 to 50 ° C.

[Step 4]
Compound (2-7) is produced by hydrolyzing compound (2-6) in the presence of an acid or a base. Examples of the acid include mineral acids such as hydrochloric acid and sulfuric acid, and examples of the base include alkali metal hydroxides (potassium hydroxide, sodium hydroxide, etc.). Examples of the solvent include water, alcohol solvents (methanol, ethanol, isopropyl alcohol, 1-butanol, etc.), ether solvents (THF, diethyl ether, DME, 1,4-dioxane, etc.), or a mixed solvent thereof. Can be mentioned. The reaction temperature is usually selected from the range of 0 to 200 ° C, preferably 50 to 150 ° C.

[Step 5]
Compound (I-1b) is produced from compound (2-7) and compound (1-4) by the same method as in Step 2 described in Production Method 1.

[Production Method 3]
In the formula (I), X ³ and X ⁴ are a group bonded to each other: -CSNH- [compound of the following formula (I-2)] and -C (R ⁹ ) = N-, R ⁹ There -S-C _1-6 alkyl, compound [compound of formula (I-3a)] can be produced, for example, by the following method.

^{(Wherein, R 1, R 2, R} 3, R 4, R 5, R 6, X 1 and X ² have the same meanings as defined in claim ^1, A 1 ^'' has the same meaning as in Production Method 1, R ¹³ Is C _1-6 alkyl.)

[Step 1]
Compound (I-2) is produced by reacting the compound (1-6) produced by Production Method 1 with a thiocarbonylating reagent in the same manner as in Step 4 described in Production Method 1. Examples of the thiocarbonylating reagent include 1,1-thiocarbonyldiimidazole, thiophosgene and the like.

[Step 2]
Compound (I-3a) is produced by reacting compound (I-2) with compound (3-1) in the presence of a base in an inert solvent. The amount of compound (3-1) to be used is generally selected from the range of 1 equivalent to excess with respect to compound (I-2). Examples of the inert solvent include ether solvents (THF, diethyl ether, DME, 1,4-dioxane, etc.), halogen solvents (methylene chloride, chloroform, etc.), aprotic polar solvents (DMF, N, N— Dimethylacetamide, DMSO, acetonitrile, etc.), ketones (acetone, etc.), or a mixed solvent thereof. Examples of the base include alkali metal carbonates (cesium carbonate, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.), alkali metal hydrides (sodium hydride, potassium hydride, etc.), alkali metal hydroxides (hydroxide) Potassium, sodium hydroxide, etc.), alkali metal alkoxides (sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), organic bases (N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [ 5.4.0] Undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, etc. ). The amount of the base used is usually selected from the range of 1 to 5 equivalents relative to compound (I-2). The reaction temperature is usually selected from the range of −78 to 100 ° C., preferably 0 to 100 ° C.

[Production Method 4]
In the formula (I), compounds in which X ³ and X ⁴ are groups bonded to each other: —C (R ⁹ ) ═N— [compounds of the following formulas (I-3b) and (I-3c)] are, for example, It can be produced according to the following method.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , X ¹ and X ² are as defined in item 1; R ¹⁴ is C _1-6 alkyl. R ⁹⁴ is a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy, aryl or heteroaryl, and A ³ is a chlorine atom, a hydroxyl group or NH _2. )

[Step 1]
By reacting the compound (1-6) produced by Production Method 1 with a trialkyl orthocarboxylate (4-1) or acid chloride (4-2) in the presence or absence of a base or acid, Compound (I-3b) can be produced. The amount of compound (4-1) and compound (4-2) to be used is generally selected from the range of 1 equivalent to excess with respect to compound (1-6). Examples of the base include organic bases (N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0]. Nona-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, etc.), and examples of the acid include mineral acids such as hydrochloric acid and sulfuric acid, or acetic acid and formic acid. And organic acids such as trifluoroacetic acid. Examples of the solvent include ether solvents (THF, diethyl ether, DME, 1,4-dioxane, etc.), aprotic solvents (toluene, etc.), halogen solvents (methylene chloride, chloroform, etc.), aprotic polar solvents. (DMF, N, N-dimethylacetamide, DMSO, acetonitrile, etc.), ketones (acetone, etc.), or a mixed solvent thereof may be mentioned, but the reaction may be carried out without solvent. The reaction temperature is usually selected from the range of −78 to 200 ° C., preferably 0 to 200 ° C. You may utilize a microwave as needed.

[Step 2]
Compound (I-3c) can be produced by reacting compound (1-6) with compound (4-3). The amount of compound (4-3) to be used is generally selected from the range of 1 equivalent to excess with respect to compound (1-6). Examples of the solvent include ether solvents (THF, diethyl ether, DME, 1,4-dioxane, etc.), halogen solvents (methylene chloride, chloroform, etc.), aprotic polar solvents (DMF, N, N-dimethylacetamide). , DMSO, acetonitrile, etc.), ketones (acetone, etc.), or mixed solvents thereof, and if necessary, carbodiimides such as condensing agents (dicyclohexylcarbodiimide, 1-ethyl-3- (dimethylaminopropyl) carbodiimide, BOP Phosphonium salts such as HBTU, etc.), additives (1-hydroxybenzotriazole, etc.), bases (N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0). ] Undeca-7-D , 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, etc.) may be used. The reaction temperature is usually selected from the range of −78 to 200 ° C., preferably 0 to 200 ° C. You may utilize a microwave as needed.

[Production Method 5]
In the formula (I), compounds in which X ³ and X ⁴ are bonded to each other: —C (R ⁹ ) ═N—, R ⁵ is NHR ¹⁰ and X ² is a nitrogen atom [the following formula ( Compounds of I-3d) and (I-3e)] can be produced, for example, according to the following method.

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁹ , R ¹⁰ and X ¹ are as defined in item 1; A ¹ , A ^{1 ′} , A ^{1 ″} and M are manufactured) As defined in Method 1, A ^{1 ′ ″} is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, OMs, OTs, or OTf, and P ¹ is a protecting group such as a 2-tetrahydropyranyl group. is there.)
[Step 1]
Compound (5-2) is produced from compound (5-1) and compound (2-1) by the same method as in Step 1 described in Production Method 2.
[Step 2]
Compound (5-3) is produced from compound (5-2) and compound (2-4) by the same method as in Step 2 described in Production Method 2.
[Step 3]
Compound (5-4) is produced from compound (5-3) and compound (1-4) by the same method as in Step 2 described in Production Method 1.
[Step 4]
For example, by using the general deprotection conditions shown in the literature (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)), compound (5-4) is converted to compound (I-3d). ) Is manufactured.
[Step 5]
Compound (I-3e) is produced from compound (I-3d) and compound (2-2) by the same method as in Step 1 described in Production Method 2.
[Step 6]
Compound (I-3e) is a compound (5-5) produced by the same method as in step 1 and step 2 of compound (1-4) and production method 2 by the same method as in step 2 described in production method 1. ) And can also be manufactured.

[Production Method 6]
In the formula (I), a compound in which X ³ and X ⁴ are groups bonded to each other: —CH═CH— [compound of the following formula (I-4)] can be produced, for example, according to the following method.

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X ¹ and X ² have the same meanings as in item 1, and A ¹ , A ^{1 ′} , A ^{1 ″} , A ^{1 ′ '' And} M are synonymous with production method 5, and R ¹⁴ is synonymous with production method 4.)

[Step 1]
Compound (6-2) is produced by reacting compound (6-1) with ammonia. Examples of the solvent include ether solvents (THF, diethyl ether, DME, 1,4-dioxane, etc.), aprotic polar solvents (DMF, N, N-dimethylacetamide, DMSO, acetonitrile, etc.), water, alcohols, and the like. A solvent (methanol, ethanol, etc.), ketones (acetone, etc.), or a mixed solvent thereof can be mentioned. The reaction temperature is usually selected from the range of −78 to 150 ° C., preferably 0 to 50 ° C.

[Step 2]
Compound (6-4) is produced by obtaining a coupling product from compound (6-2) and compound (6-3) in the same manner as in Step 2 described in Production Method 1, and subsequently heating. Examples of the solvent include an acidic solvent (such as acetic acid), an aprotic solvent (such as toluene), an ether solvent (such as THF, diethyl ether, DME, and 1,4-dioxane), and an aprotic polar solvent (such as DMF and N). , N-dimethylacetamide, DMSO, acetonitrile, etc.), water, alcohol solvents (methanol, ethanol, etc.), ketones (acetone, etc.), or a mixed solvent thereof. The reaction temperature is usually selected from the range of 0 to 200 ° C, preferably 50 to 150 ° C.

[Step 3]
Compound (6-5) is produced from compound (6-4) and compound (2-2) by the same method as in Step 1 described in Production Method 2.
[Step 4]
Compound (I-4) is produced from compound (6-5) and compound (1-4) by the same method as in Step 2 described in Production Method 1.

[Production Method 7]
In the formula (I), X ³ is a hydrogen atom, X ⁴ is a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxycarbonyl, carboxyl or —CONR ¹¹ R ¹² , and X ² is nitrogen In the compound which is an atom [compound of the following formula (I-5a)] and formula (I), X ³ is a hydrogen atom, X ⁴ is C _1-6 alkyl, and X ² is a nitrogen atom. The compound [compound of the following formula (I-5b)] can be produced, for example, according to the following method.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X ¹ are as defined in item 1, A ¹ , A ^{1 ′} and M are as defined in production method 1; ⁴¹ is a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxycarbonyl, carboxyl, —CONR ¹¹ R ¹² or a leaving group (OMs, OTs, OTf, etc.), and X ⁴² is a hydrogen atom , A halogen atom, C _1-6 alkyl, C _1-6 alkoxycarbonyl, carboxyl or —CONR ¹¹ R ¹² , X ⁴³ is C _1-6 alkyl, and M ′ is a cross of tin, boron or zinc (The metal used in the coupling reaction.)

[Step 1]
Compound (7-2) is produced from compound (7-1) and compound (1-2) by the same method as in Step 1 described in Production Method 1.
[Step 2]
Compound (I-5a) is produced from compound (7-2) and compound (1-4), wherein X ⁴¹ is a group other than a leaving group, by the same method as in Step 2 described in Production Method 1.
[Step 3]
Compound (7-4) is produced by coupling reaction of an alkyl group using compound (7-3) to compound (7-2) wherein X ⁴¹ is a halogen atom or a leaving group. As the manufacturing method, the same method as in step 2 described in manufacturing method 1 is used.
[Step 4]
Compound (I-5b) is produced from compound (7-4) and compound (1-4) by the same method as in Step 2 described in Production Method 1.

  The raw material compound (1-4) containing an imidazopyridine ring used in production methods 1 to 7 can be produced, for example, according to the following method.

(In the formula, R ¹ , R ² , R ³ , R ⁴ and X ¹ are as defined in item 1, M and A ^{1 ″} are as defined in production method 1, and A ² is as defined in production method 2. is there.)

[Step 1]
Compound (8-3) is a known compound or a compound obtained by a known method (8-1) and compound (8-2) are reacted in the presence or absence of a base. Manufactured by. The amount of compound (8-2) to be used is generally 1 equivalent to an excess amount relative to compound (8-1). Examples of the solvent include alcohol solvents (ethanol, methanol, etc.), water, ether solvents (THF, diethyl ether, DME, 1,4-dioxane, etc.), aprotic polar solvents (DMF, N, N-dimethyl). Acetamide, DMSO, acetonitrile, etc.) or a mixed solvent thereof. When a base is used, for example, alkali metal carbonate (cesium carbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, etc.), organic base (N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8- Diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, Pyridine etc.) are used. The reaction temperature is usually selected from the range of 0 to 200 ° C, preferably 50 to 150 ° C.

[Step 2]
Compound (8-4) is obtained by reacting compound (8-3) with a halogenating agent. Examples of the halogenating agent include chlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and the like. The amount of the halogenating agent to be used is usually selected from the range of 1 equivalent to excess with respect to compound (8-3). Examples of the solvent include chlorinated solvents (chloroform, methylene chloride, etc.), ether solvents (THF, diethyl ether, DME, 1,4-dioxane, etc.), aprotic polar solvents (DMF, N, N-dimethylacetamide). , DMSO, acetonitrile, etc.), ketones (acetone, etc.), or a mixed solvent thereof. The reaction temperature is usually selected from the range of −78 to 100 ° C., preferably 0 to 50 ° C.

[Step 3]
Compound (1-4) is produced by reacting compound (8-4) with an organometallic reagent in an inert solvent, performing metal-halogen exchange, and then transmetalating with the second metal reagent. Is done. Examples of the organometallic reagent include organomagnesium reagents (isopropyl magnesium chloride, etc.) and organolithium reagents (butyllithium, methyllithium, etc.). Examples of the second metal reagents include organotin reagents (tributyltin chloride, etc.). ), Boron reagents (trimethyl borate, etc.), zinc reagents (zinc bromide, zinc iodide, etc.). Examples of the inert solvent include ether solvents (THF, diethyl ether, etc.). As reaction temperature, it can select normally from the range of -100-100 degreeC, Preferably the range of -78-50 degreeC is mentioned.
It is also possible to prepare compound (1-4) by allowing an activated metal to act on compound (8-4) in an inert solvent. Examples of the activated metal include activated zinc (Rieke zinc and the like). Examples of the inert solvent include ether solvents (THF, diethyl ether, etc.), and the reaction temperature can usually be selected from the range of −78 ° C. to 100 ° C., preferably 0 ° C. to 100 ° C. A range of ° C is mentioned.
As still another production method, compound (1-4) can be produced by reacting compound (8-4) with a metal reagent in the presence or absence of a base and in the presence of a transition metal catalyst. Examples of transition metal catalysts include palladium catalysts (palladium acetate, tris (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, etc. And a ligand may be used if necessary. Examples of the ligand include a phosphine ligand (triphenylphosphine, tri (t-butyl) phosphine, trifurylphosphine, etc.), a carbene ligand (1,3-bis (2,6-diisopropylphenyl) imidazole). 2-ylidene and the like). Examples of the base include alkali metal carbonates (cesium carbonate, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.), alkali metal hydroxides (potassium hydroxide, sodium hydroxide, etc.), alkali metal alkoxides (sodium ethoxide). , Sodium tert-butoxide, potassium tert-butoxide, etc.), organic base (N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5 -Diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine and the like). Further, for example, an additive such as an alkali metal fluoride (such as cesium fluoride) may be used. Examples of the metal reagent include a tin reagent (such as hexabutyl distanane) and a boron reagent (such as bis (pinacolato) diborane). Examples of the solvent include ether solvents (THF, diethyl ether, DME, 1,4-dioxane, etc.), aprotic solvents (toluene, etc.), aprotic polar solvents (DMF, N, N-dimethylacetamide, DMSO). , Acetonitrile, etc.), water, alcohol solvents (methanol, ethanol, etc.), or a mixed solvent thereof. As reaction temperature, it can select normally from the range of 0-200 degreeC, Preferably the range of 50-150 degreeC is mentioned.

In the above reaction, the functional group of each compound can be protected as necessary. As the protecting group, a known protecting group (Protective Groups in Organic Synthesis, TWGreene, A
Wiley-Interscience Publication (1999)) can be used.
The raw materials and reagents used in the above reaction are commercially available compounds or can be produced from known compounds using known methods unless otherwise specified.

  Compound (I) produced according to the above production method may be obtained as a mixture of isomers. In that case, it can be isolated and purified by an ordinary method such as chromatography, recrystallization, reprecipitation, etc., with the example compound or intermediate raw material compound. In addition, when the compound of formula (I) is a racemate, according to a conventional method such as an optical resolution method by chromatography using an optically active column, a preferential crystallization method, a diastereomer method, etc. And can be separated and purified.

  The pharmaceutically acceptable salt of Compound (I) is a pharmaceutically acceptable salt of Compound (I) such as hydrochloric acid, citric acid or methanesulfonic acid in a solvent such as water, methanol, ethanol or acetone. It can be obtained by mixing with an acid. When an acidic functional group such as carboxylic acid is present in Compound (I), a pharmaceutically acceptable salt of Compound (I) is obtained by reacting Compound (I) in a solvent such as water, methanol or ethanol. It can be obtained by mixing with a pharmaceutically acceptable base such as sodium hydroxide, lithium hydroxide or potassium hydroxide.

  Since the compound of the present invention has a JAK inhibitory action, it can be used as a therapeutic or prophylactic agent for the following diseases caused by undesirable cytokine signals. Rejection associated with organ and tissue transplantation; graft-versus-host reaction after bone marrow transplantation; rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (scleroderma), polymyositis, dermatomyositis, inclusion myositis, side Vasculitis syndromes such as cranial arteritis, polyarteritis nodosa, mixed connective tissue disease, Behcet's disease, Sjogren's syndrome, Hashimoto's disease, Passow's disease, type I diabetes, Addison's disease, multigland autoimmune syndrome, autoimmunity Hemolytic anemia, autoimmune thrombocytopenia, multiple sclerosis, myasthenia gravis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, pernicious anemia, Goodpasture syndrome, pemphigus, Autoimmune diseases and rheumatic diseases such as psoriasis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, reactive arthritis, psoriatic arthritis; allergic asthma, atopic dermatitis (eczema), allergic rhinitis Hay fever), allergic urticaria, angioedema, food allergy, anaphylaxis, allergic contact dermatitis, cell-mediated hypersensitivity, hypersensitivity pneumonia, etc .; Epstein-Barr virus (EBV), B Viral diseases such as hepatitis C, hepatitis C, HIV, HTLV1, varicella-zoster virus (VZV), human papilloma virus (HPV); leukemia, lymphoma, prostate cancer, multiple myeloma, hepatocellular carcinoma, kidney Cancer diseases such as cancer, pancreatic cancer, gastric cancer, breast cancer, glioblastoma and the like can be mentioned.

  The compound of the present invention can be administered orally or parenterally (intramuscular, intravenous, subcutaneous, transdermal, intranasal, suppository, eye drop, intracerebral administration). Examples of the dosage form include generally accepted dosage forms, such as powders, granules, fine granules, tablets, capsules, pills, syrups, suspensions, liquid injections, emulsions, Rectal suppositories, transdermal agents (ointments, creams, lotions, etc.) and the like can be mentioned.

  At the time of formulation, it can be produced by a conventional method using an ordinary carrier or diluent. A solid preparation such as a tablet comprises an active compound, a pharmaceutically acceptable carrier or excipient (lactose, sucrose, corn starch, etc.), a binder (hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.), It can be produced by mixing a disintegrating agent (sodium carboxymethylcellulose, sodium starch glycolate, etc.), a lubricant (stearic acid, magnesium stearate, etc.) or a preservative. When preparing parenteral preparations such as solutions and suspensions, the active compound is dissolved or suspended in a physiologically acceptable carrier or diluent such as water, physiological saline, oil or dextrose solution. If necessary, auxiliary agents such as a pH adjuster, a buffer, a stabilizer, a solubilizer, an emulsifier, and an osmotic pressure adjuster can be added.

  The dose and frequency of administration of the compound of the present invention generally vary depending on the route of administration, the degree of symptoms, body weight and the like. The compound of the present invention is usually about 0.1 mg to about 1 g, preferably about 1 mg to about 500 mg, more preferably about 5 mg to about 200 mg once a day in an adult (body weight 60 kg) when orally administered. It is administered more frequently. In addition, administration once every two days to one week is also possible.

  Hereinafter, the present invention will be described more specifically with reference to reference examples, examples, and test examples, but these examples do not limit the present invention. The compound was identified by elemental analysis, mass spectrum, high performance liquid chromatography / mass spectrometer; LCMS, IR spectrum, NMR spectrum, high performance liquid chromatography (HPLC) and the like.

  In order to simplify the description of the specification, the following abbreviations may be used in the examples and tables in the examples. As symbols used in NMR, s is a single line, d is a double line, t is a triple line, q is a quadruple line, m is a multiple line, and br is gentle.

High-performance liquid chromatograph / mass spectrometer; LCMS measurement conditions are as follows, and the observed mass spectrometry value [MS (m / z)] is represented by M + H, and the retention time is represented by T (min).
MS detector: Waters micromass ZQ
HPLC: Waters2790 separations module
Column: Impact Cadenza CD-C18 2.0mm x 20mm
Flow rate: 1.0 ml / min
Measurement wavelength: 254 nm
Moving bed: A liquid; water B liquid; acetonitrile C liquid; 2% formic acid acetonitrile solution Time program:
Step Time (min) A liquid: B liquid: C liquid
1 0.0 -0.1 95: 2: 3
2 0.1 -3.1 95: 2: 3 → 1: 96: 3
3 3.1 -3.5 1: 96: 3

Reference example 1
3-Bromo-6-methylimidazo [1,2-a] pyridine (1) 6-Methylimidazo [1,2-a] pyridine To 2-amino-5-methylpyridine (1.00 g, 9.25 mmol), Ethanol (10 mL) and 40% aqueous chloroacetaldehyde solution (2.70 g, 13.8 mmol) were added, and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered, and then the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to 0/1 → chloroform / methanol = 20/1) to obtain the title compound (1.22 g, 100%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.90 (s, 1H), 7.58 (s, 1H), 7.53 (d, 1H, J = 9.4 Hz), 7.50 (s, 1H), 7.02 (d, 1H , J = 9.4 Hz), 2.31 (s, 3H). LC / MS: T = 0.31, m / z = 133 (M + H) ⁺ .

(2) 3-Bromo-6-methylimidazo [1,2-a] pyridine 6-Methylimidazo [1,2-a] pyridine (500 mg, 3.78 mmol) in chloroform (10 mL) in 1-bromos Acid imide (670 mg, 3.76 mmol) was added and stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to 0/1) to give the title compound (744 mg, 93%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.90 (d, 1H, J = 1.6 Hz), 7.56 (s, 1H), 7.52 (d, 1H, J = 9.2 Hz), 7.09 (dd, 1H, J = 1.6, 9.2 Hz), 2.39 (s, 3H).

Reference example 2
3-Bromo-6-fluoroimidazo [1,2-a] pyridine (1) In the same manner as in 6-fluoroimidazo [1,2-a] pyridine Reference Example 1- (1), 2-amino-5- Synthesized from fluoropyridine.
LC / MS: T = 0.29, m / z = 137 (M + H) ⁺ .

(2) 3-Bromo-6-fluoroimidazo [1,2-a] pyridine Synthesized from 6-fluoroimidazo [1,2-a] pyridine in the same manner as in Reference Example 1- (2).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.07-8.08 (m, 1H), 7.67 (s, 1H), 7.61 (ddd, 1H, J = 0.6, 5.0, 9.8 Hz), 7.17 (ddd, 1H, J = 2.4, 7.9, 9.8 Hz).

Reference example 3
3-bromoimidazo [1,2-a] pyridine-6-carbonitrile (1) imidazo [1,2-a] pyridine-6-carbonitrile In the same manner as in Reference Example 1- (1), 2-amino Synthesized from -5-cyanopyridine.
LC / MS: T = 0.29, m / z = 144 (M + H) ⁺ .

(2) 3-bromoimidazo [1,2-a] pyridine-6-carbonitrile Synthesized from imidazo [1,2-a] pyridine-6-carbonitrile in the same manner as in Reference Example 1- (2). .
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.59 (dd, 1H, J = 1.0, 1.6 Hz), 7.78 (s, 1H), 7.73 (dd,
1H, J = 1.0, 9.4 Hz), 7.37 (dd, 1H, J = 1.6, 9.4 Hz).

Reference example 4
2- (4-Aminophenoxy) acetamide (1) 2- (4-Nitrophenoxy) acetamide 4-Nitrophenol (3.00 g, 21.6 mmol) was added to acetone (40 mL) and potassium carbonate (6.00 g, 43.43). 4 mmol) and 2-bromoacetamide (3.00 g, 21.7 mmol) were added, and the mixture was stirred at room temperature for 2 hours and subsequently at 50 ° C. for 9 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered, and then the filtrate was concentrated. Hexane-ethyl acetate (1: 1) was added to the residue, and the solid was collected by filtration to give the title compound (3.28 g, 77%).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 8.22 (d, 2H, J = 9.3 Hz), 7.66 (brs, 1H), 7.46 (brs, 1H), 7.14 (d, 2H, J = 9.3 Hz) ), 4.62 (s, 2H).

(2) 2- (4-Aminophenoxy) acetamide 2- (4-Nitrophenoxy) acetamide (2.00 g, 10.2 mmol) to methanol (20 mL), THF (15 mL), 10% palladium carbon (1.00 g) And stirred at room temperature for 4 hours under a hydrogen stream. After filtration through celite, the filtrate was concentrated, hexane-ethyl acetate (1: 1) was added to the residue, and the solid was collected by filtration to give the title compound (1.60 g, 94%).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 7.39 (brs, 1H), 7.34 (brs, 1H), 6.68 (d, 2H, J = 8.9 Hz), 6.50 (d, 2H, J = 8.9 Hz) ), 4.65 (s, 2H), 4.23 (s, 2H).

Example 1
9- (2,6-Difluorobenzyl) -2-imidazo [1,2-a] pyridin-3-yl-7,9-dihydro-8H-purin-8-one

(1) 2-chloro-N- (2,6-difluorobenzyl) -5-nitropyrimidin-4-amine 2,4-dichloro-5-nitropyrimidine (3.10 g, 16.0 mmol) in THF (
65 mL) solution was cooled to −78 ° C. and diisopropylmethylamine (3.00 mL, 19.7 mmol) and 2,6-difluorobenzylamine (2.40 g, 16.8 mmol) were added sequentially. The reaction was slowly warmed to room temperature and stirred overnight. 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 magnesium sulfate, filtered, and the filtrate was concentrated. Hexane-ethyl acetate (3: 1) was added to the residue, and the solid was collected by filtration to give the title compound (4.13 g, 86%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 9.05 (s, 1H), 8.62 (br, 1H), 7.33 (tt, 1H, J = 6.5, 8.4
Hz), 6.96 (dd, 2H, J = 7.9, 8.4 Hz), 4.95 (d, 2H, J = 5.6 Hz) .LC / MS: T = 2.24, m / z = 301 (M + H) ⁺ .

(2) N- (2,6-difluorobenzyl) -2-imidazo [1,2-a] pyridin-3-yl-5-nitropyrimidin-4-amine 6-bromoimidazo [1,2-a] pyridine (2.00 g, 10.2 mmol) of THF
(30 mL) The solution was cooled to −78 ° C. and 2N isopropylmagnesium chloride / THF.
(7.60 mL, 15.2 mmol) solution was added dropwise. After stirring at the same temperature for 30 minutes, tributyltin chloride (4.10 mL, 15.1 mmol) was added dropwise, and the temperature was gradually raised to room temperature to prepare a tin reagent. A portion of this tin reagent (10.0 mL) was used in the next reaction to give 2-chloro-N- (2,6-difluorobenzyl) -5-nitropyrimidin-4-amine (600 mg, 2.00 mmol), tetrakis ( Triphenylphosphine) palladium (0) (210 mg, 0.182 mmol) and toluene (10 mL) were added, and the mixture was stirred for 2 hours with heating under reflux. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered, and then the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 0/1) to give the title compound (138 mg, 18%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.93 (ddd, 1H, J = 1.1, 1.3, 6.9 Hz), 9.27 (s, 1H), 8.84 (brs, 1H), 8.81 (s, 1H), 7.80 (ddd, 1H, J = 1.1, 1.2, 9.0 Hz), 7.46 (ddd, 1H, J = 1.3, 6.9, 9.0 Hz), 7.28-7.32 (m, 1H), 7.10 (ddd, 1H, J = 1.2, 6.9, 6.9 Hz), 6.96 (dd, 1H, J = 8.0, 8.0 Hz), 5.09 (d, 2H, J = 6.0 Hz). LC / MS: T = 2.13, m / z = 383 (M + H) ⁺ .

(3) N ⁴ - (2,6- difluorobenzyl) -2-imidazo [1,2-a] pyridin-3-yl-pyrimidin-4,5-diamine N-(2,6-difluorobenzyl) -2- To a solution of imidazo [1,2-a] pyridin-3-yl-5-nitropyrimidin-4-amine (160 mg, 0.418 mmol) in methanol (5.0 mL) was added 10% palladium on carbon (50% wet) (110 mg). ) And stirred for 3 hours at room temperature under a hydrogen stream. After filtration through celite, the filtrate was concentrated to give the title compound (147 mg, 100%).
LC / MS: T = 1.74, m / z = 353 (M + H) ⁺ .

(4) 9- (2,6-difluorobenzyl) -2-imidazo [1,2-a] pyridin-3-yl-7,9-dihydro--8H- purin-8-one N ⁴ - (2, 6 -Difluorobenzyl) -2-imidazo [1,2-a] pyridin-3-ylpyrimidine-4,5-diamine (110 mg, 0.312 mmol) and THF (4.
0 mL) and 1,1′-carbonyldiimidazole (150 mg, 0.925 mmol) were added and stirred at room temperature overnight. The reaction mixture was concentrated, methanol-ethyl acetate (1: 1) was added to the residue, and the solid was collected by filtration to give the title compound (72.0 mg, 61%).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 11.53 (brs, 1H), 9.73 (d, 1H, J = 7.0 Hz), 8.34 (s, 1H), 8.28 (s, 1H), 7.73 (d , 1H, J = 9.0 Hz), 7.39-7.45 (m, 2H), 7.13-7.18 (m, 3H), 5.18 (s, 2H). LC / MS: T = 1.75, m / z = 379 (M + H) ⁺ .

Example 2-80
Using the corresponding starting material compounds, the compounds shown in Tables 1 to 4 were obtained in the same manner as in Example 1.

Example 81
[4- (2-Imidazo [1,2-a] pyridin-3-yl-8-oxo-7,8-dihydro-9H-purin-9-yl) phenoxy] acetonitrile

(1) 2- {4-[(2-Chloro-5-nitropyrimidin-4-yl) amino] phenoxy} acetamide In the same manner as in Example 1- (1), 2,4-dichloro-5-nitro Synthesized from pyrimidine and 2- (4-aminophenoxy) acetamide (Reference Example 4).
LC / MS: T = 1.80, m / z = 324 (M + H) ⁺ .

(2) 2- {4-[(2-Imidazo [1,2-a] pyridin-3-yl-5-nitropyrimidin-4-yl) amino] phenoxy} acetamide Similar to Example 1- (2) Method from 6-bromoimidazo [1,2-a] pyridine and 2- {4-[(2-chloro-5-nitropyrimidin-4-yl) amino] phenoxy} acetamide (140 mg, 0.433 mmol) To give a mixture containing the title compound.
LC / MS: T = 1.60, m / z = 406 (M + H) ⁺ .

(3) {4-[(2-Imidazo [1,2-a] pyridin-3-yl-5-nitropyrimidin-4-yl) amino] phenoxy} acetonitrile 2- {4-[(2-Imidazo [1 , 2-a] pyridin-3-yl-5-nitropyrimidin-4-yl) amino] phenoxy} acetamide in pyridine solution (4.0 mL) under ice cooling with dropwise addition of trifluoroacetic anhydride (2.0 mL). And stirred at the same temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, extracted with chloroform, dried over magnesium sulfate, filtered, and then the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain a mixture containing the title compound.
LC / MS: T = 1.99, m / z = 388 (M + H) ⁺ .

(4) [4- (2-Imidazo [1,2-a] pyridin-3-yl-8-oxo-7,8-dihydro-9H-purin-9-yl) phenoxy] acetonitrile {4-[(2 -Imidazo [1,2-a] pyridin-3-yl-5-nitropyrimidin-4-yl) amino] phenoxy} acetonitrile in a mixture of ethanol (1 mL) -water (1 mL) with acetic acid (7. 0 μl, 0.117 mmol) and reduced iron (12.0 mg, 0.195 mmol) were added, and the mixture was stirred with heating under reflux for 1 hour. The reaction mixture was allowed to cool to room temperature, insoluble matters were filtered off, and the filtrate was concentrated. To the residue was added saturated aqueous sodium hydrogen carbonate, extracted with chloroform, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in THF (1.00 mL), 1,1′-carbonyldiimidazole (13.0 mg, 0.0780 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 97/3) to obtain the title compound (2.00 mg, 1%, 4 steps).
¹ H-NMR (CDCl ₃ , 300 MHz) δ 9.87 (d, 1H, J = 7.2 Hz), 8.43 (s, 1H), 8.35 (s, 1H), 7.81 (d, 2H, J = 9.0 Hz), 7.67 (d, 1H, J = 9.0 Hz), 7.44 (ddd, 1H, J = 1.3, 6.8, 9.0 Hz), 7.31 (d, 2H, J = 9.0 Hz), 7.07 (ddd, 1H, J = 1.1, 6.8, 7.2 Hz), 5.11 (s, 2H) .LC / MS: T = 1.68, m / z = 384 (M + H) ⁺ .

Example 82
9- (2,6-Difluorobenzyl) -2-imidazo [1,2-a] pyridin-3-yl-7-methyl-7,9-dihydro-8H-purin-8-one

9- (2,6-difluorobenzyl) -2-imidazo [1,2-a] pyridin-3-yl-7,9-dihydro-8H-purin-8-one (20.0 mg, 0.0529 mmol, carried out) To Example 1), a DMF solution (0.5 mL), potassium carbonate (20 mg, 0.145 mmol) and a prepared 0.803 N methyl iodide / DMF solution (0.070 mL, 0.0562 mmol) were sequentially added, and 70 ° C. For 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate-toluene (1: 1). The organic layer was washed twice with water, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 20/1) to obtain the title compound (7.9 mg, 38%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.82 (ddd, 1H, J = 1.1, 1.1, 7.0 Hz), 8.48 (s, 1H), 8.19 (s, 1H), 7.71 (ddd, 1H, J = 1.1, 1.1, 9.0 Hz), 7.23-7.33 (m, 2H), 6.97 (ddd, 1H, J = 1.1, 7.0, 7.0 Hz), 6.92 (dd, 2H, J = 8.0, 8.0 Hz), 5.30 (s , 2H), 3.50 (s, 3H) .LC / MS: T = 1.76, m / z = 393 (M + H) ⁺ .

Example 83
9- (2,6-Difluorobenzyl) -7- [2- (dimethylamino) ethyl] -2-imidazo [1,2-a] pyridin-3-yl-7,9-dihydro-8H-purine-8 -ON

9- (2,6-difluorobenzyl) -2-imidazo [1,2-a] pyridin-3-yl-7,9-dihydro-8H-purin-8-one (20.0 mg, 0.0529 mmol, carried out) To Example 1), a DMF solution (1.0 mL), 60% sodium hydride (6.0 mg, 0.15 mmol) and 2-dimethylaminoethyl chloride hydrochloride (10.0 mg, 0.0694 mmol) were sequentially added. Stir at 4 ° C. for 4 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate-toluene (1: 1). The organic layer was washed twice with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 20/1) to obtain the title compound (13.3 mg, 56%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.82 (ddd, 1H, J = 1.1, 1.1, 7.0 Hz), 8.48 (s, 1H), 8.28 (s, 1H), 7.71 (ddd, 1H, J = 1.1, 1.1, 9.0 Hz), 7.23-7.33 (m, 2H), 6.97 (ddd, 1H, J = 1.1, 7.0, 7.0 Hz), 6.92 (dd, 2H, J = 8.0, 8.0 Hz), 5.30 (s , 2H), 4.02 (t, 2H, J = 6.4 Hz), 2.68 (t, 2H, J = 6.4 Hz), 2.31 (s, 6H). LC / MS: T = 1.56, m / z = 225 (bp ), 450 (M + H) ⁺ .

Examples 84-108
Using the corresponding starting material compounds, the compounds shown in Table 5 were obtained in the same manner as in Example 82 or Example 83.

Example 109
2-Imidazo [1,2-a] pyridin-3-yl-7- (1-phenylethyl) -7H-pyrrolo [2,3-d] pyrimidine

(1) 5-bromo-2-chloropyrimidin-4-amine 5-bromo-2,4-dichloropyrimidine (400 mg, 1.76 mmol) in THF (22.0 mL) was added to a 30% aqueous ammonia solution (3.0 mL). ) And stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted with chloroform, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give the title compound (180 mg, 49%).
LC / MS: T = 0.74, m / z = 208, 210 (M + H) ⁺ .

(2) 2-chloro-5-[(Z) -2-ethoxyvinyl] pyrimidin-4-amine 5-bromo-2-chloropyrimidin-4-amine (100 mg, 0.480 mmol) in toluene (1.2 mL) ) Was added (Z) -1-ethoxy-2- (tributylstannyl) ethene (260 mg, 0.720 mmol) and tetrakis (triphenylphosphine) palladium (0) (111 mg, 0.0960 mmol), and heated under reflux. Stir for 2 hours. The reaction mixture was allowed to cool to room temperature, water was added, the mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to obtain a crude product of the title compound (68.0 mg).
LC / MS: T = 1.65, m / z = 200 (M + H) ⁺ .

(3) 2-Chloro-7H-pyrrolo [2,3-d] pyrimidine Acetic acid of crude product (68.0 mg) of 2-chloro-5-[(Z) -2-ethoxyvinyl] pyrimidin-4-amine The solution (3.0 mL) was stirred at 100 ° C. for 3 hours. The reaction solution was allowed to cool to room temperature, and toluene was added to concentrate the reaction solution. Ethyl acetate was added to the residue, and the resulting solid was stirred for 1 hour at room temperature. The resulting solid was collected by filtration to give the title compound (40.0 mg, 55%, 2 steps).
¹ H-NMR (CDCl ₃ , 300 MHz) δ 8.81 (s, 1H), 7.36 (d, 1H, J = 3.7 Hz), 6.60 (d, 1H, J = 3.7 Hz). LC / MS: T = 0.66 , m / z = 154 (M + H) ⁺ .

(4) 2-chloro-7- (1-phenylethyl) -7H-pyrrolo [2,3-d] pyrimidine 2-chloro-7H-pyrrolo [2,3-d] pyrimidine (40.0 mg, 0.260 mmol) ) Was added to a DMF solution (1.3 mL) of potassium carbonate (108 mg, 0.780 mmol) and (1-bromoethyl) benzene (72.0 mg, 0.390 mmol), and the mixture was stirred at 40 ° C. for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give the title compound (50.0 mg, 75%).
LC / MS: T = 2.23, m / z = 258 (M + H) ⁺ .

(5) 2-Imidazo [1,2-a] pyridin-3-yl-7- (1-phenylethyl) -7H-pyrrolo [2,3-d] pyrimidine The same method as in Example 1- (2) And synthesized from 6-bromoimidazo [1,2-a] pyridine and 2-chloro-7- (1-phenylethyl) -7H-pyrrolo [2,3-d] pyrimidine.
¹ H-NMR (CDCl ₃ , 300 MHz) δ 9.88 (d, 1H, J = 7.2 Hz), 9.01 (s, 1H), 8.61 (s, 1H), 7.74 (d, 1H, J = 9.0 Hz), 7.27-7.39 (m, 7H), 6.95 (ddd, 1H, J = 1.3, 7.2, 7.2 Hz), 6.59 (d, 1H, J = 3.7 Hz), 6.22 (q, 1H, J = 7.2 Hz), 1.99 (d, 3H, J = 7.2 Hz) .LC / MS: T = 1.94, m / z = 340 (M + H) ⁺ .

Example 110
2-Imidazo [1,2-a] pyridin-3-yl-7-methyl-N- (1-phenylethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine

(1) 2,4-Dichloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidine DMF of 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (188 mg, 1.00 mmol) To the solution (5.0 mL) was added 60% sodium hydride (80.0 mg) under ice cooling.
, 2.00 mmol), and stirred at the same temperature for 10 minutes. Subsequently, methyl iodide (0.125 mL, 2.00 mmol) was added, and the mixture was stirred for 1 hour under ice cooling. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with chloroform, dried over magnesium sulfate, filtered, and the filtrate was concentrated. Ethyl acetate was added to the residue and stirred, and the resulting solid was collected by filtration to give the title compound (190 mg, 94%).
LC / MS: T = 1.94, m / z = 202 (M + H) ⁺ .

(2) 2-Chloro-7-methyl-N- (1-phenylethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine 2,4-dichloro-7-methyl-7H-pyrrolo [2 , 3-d] pyrimidine (35.0 mg, 0.173 mmol) in water (0.8 mL) -1,4-dioxane (0.8 mL) mixed with potassium carbonate (120 mg, 0.865 mmol) and DL-1 -Phenylethylamine (63.0 mg, 0.519 mmol) was added, and the mixture was stirred for 3 hours with heating under reflux. The reaction mixture was allowed to cool to room temperature, water was added, the mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give the title compound (30.0 mg, 60%).
LC / MS: T = 2.23, m / z = 287 (M + H) ⁺ .

(3) 2-Imidazo [1,2-a] pyridin-3-yl-7-methyl-N- (1-phenylethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine Example 1 In the same manner as in (2), 6-bromoimidazo [1,2-a] pyridine and 2-chloro-7-methyl-N- (1-phenylethyl) -7H-pyrrolo [2,3-d] Synthesized from pyrimidine-4-amine.
¹ H-NMR (CDCl ₃ , 300 MHz) δ 9.74 (d, 1H, J = 6.7 Hz), 8.46 (s, 1H), 7.67 (d, 1H, J = 9.2 Hz), 7.49 (d, 2H, J = 7.4 Hz), 7.37 (dd, 2H, J = 7.4, 7.4 Hz), 7.28-7.17 (m, 2H), 6.91 (d, 1H, J = 3.5 Hz), 6.81 (dd, 1H, J = 6.7, 6.7 Hz), 6.35 (d, 1H, J = 3.5 Hz), 5.53 (m, 1H), 5.27 (br, 1H), 3.86 (s, 3H), 1.71 (d, 3H, J = 6.6 Hz). LC /MS:T=1.95, m / z = 369 (M + H) ⁺ .

Example 111
9- (2,6-Difluorobenzyl) -2-imidazo [1,2-a] pyridin-3-yl-9H-purine

N ⁴ - (2,6-difluorobenzyl) -2-imidazo [1,2-a] pyridin-3-yl-pyrimidin-4,5-diamine (35.0mg, 0.0993mmol, Example 1- (3) ) Were added triethyl orthoformate (2.0 mL) and ethanol (1.5 mL), and the mixture was stirred at 150 ° C. for 2 hours under microwave irradiation. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol = 20/1) to give the title compound (20.8 mg, 58%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ 10.08 (ddd, 1H, J = 1.0, 1.0, 7.0 Hz), 9.14 (s, 1H), 8.68 (s, 1H), 8.18 (s, 1H), 7.75 (ddd, 1H, J = 1.0, 1.0, 9.0 Hz), 7.31-7.38 (m, 2H), 7.05 (ddd, 1H, J = 1.0, 7.0, 7.0 Hz), 6.98 (dd, 2H, J = 8.0, 8.0 Hz), 5.59 (s, 2H) .LC / MS: T = 1.76, m / z = 363 (M + H) ⁺ .

Examples 112-118
Using the corresponding starting material compounds, the compounds shown in Tables 6 to 7 were obtained in the same manner as in Example 111.

Example 119
2-Imidazo [1,2-a] pyridin-3-yl-N- (1-phenylethyl) -9H-purin-6-amine

(1) 2-Chloro-N- (1-phenylethyl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine Literature (J. Med. Chem. 2006, 49, 2861) ) Was synthesized in a DMF solution (10 mL) of 2,6-dichloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (546 mg, 2.00 mmol) synthesized according to .00 mmol) and DL-1-phenylethylamine (242 mg, 2.00 mmol) were added, and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, water was added, the mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain the title compound (700 mg, 98%).
LC / MS: T = 2.31, m / z = 358 (M + H) ⁺ .

(2) 2-Imidazo [1,2-a] pyridin-3-yl-N- (1-phenylethyl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine In a manner similar to Example 1- (2), 6-bromoimidazo [1,2-a] pyridine and 2-chloro-N- (1-phenylethyl) -9- (tetrahydro-2H-pyran-2-yl) ) -9H-purin-6-amine (36.0 mg, 0.100 mmol) gave the crude title compound (10.0 mg).
LC / MS: T = 1.98, m / z = 440 (M + H) ⁺ .

(3) 2-Imidazo [1,2-a] pyridin-3-yl-N- (1-phenylethyl) -9H-purin-6-amine 2-Imidazo [1,2-a] pyridin-3-yl To a chloroform solution (0.5 mL) of a crude product of -N- (1-phenylethyl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (10.0 mg), Trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) to obtain the title compound (1.20 mg, 3%, 2 steps).
¹ H-NMR (CDCl ₃ , 300 MHz) δ 9.38 (d, 1H, J = 6.6 Hz), 8.89 (s, 1H), 7.96 (s, 1H), 7.71 (d, 1H, J = 9.0 Hz), 7.50 (d, 2H, J = 7.3 Hz), 7.39 (dd, 2H, J = 7.3, 7.3 Hz), 7.26-7.30 (m, 1H), 6.76 (dd, 1H, J = 6.6, 6.6 Hz), 6.34 (br, 1H), 5.48 (br, 1H), 1.73 (d, 3H, J = 7.0 Hz) .LC / MS: T = 1.79, m / z = 356 (M + H) ⁺ .

Example 120
9-Benzyl-2-imidazo [1,2-a] pyridin-3-yl-N- (1-phenylethyl) -9H-purin-6-amine

(1) 9-Benzyl-2,6-dichloro-9H-purine To a solution of 2,6-dichloropurine (1.00 g, 5.29 mmol) in N, N-dimethylformamide (26 mL), potassium carbonate (2.19 g) , 15.9 mmol) and benzyl chloride (1.00 g, 7.94 mmol) were added, and the mixture was stirred at 40 ° C. for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give the title compound (800 mg, 54%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ 8.07 (s, 1H), 7.25-7.44 (m, 5H), 5.42 (s, 2H). LC / MS: T = 2.12, m / z = 279 (M + H) ⁺ .

(2) 9-Benzyl-2-chloro-N- (1-phenylethyl) -9H-purin-6-amine In the same manner as in Example 110- (2), 9-benzyl-2,6-dichloro- Synthesized from 9H-purine and DL-1-phenylethylamine.
LC / MS: T = 2.41, m / z = 364 (M + H) ⁺ .

(3) 9-Benzyl-2-imidazo [1,2-a] pyridin-3-yl-N- (1-phenylethyl) -9H-purin-6-amine The same method as in Example 1- (2) And synthesized from 6-bromoimidazo [1,2-a] pyridine and 9-benzyl-2-chloro-N- (1-phenylethyl) -9H-purin-6-amine.
¹ H-NMR (CDCl ₃ , 300 MHz) δ 9.54 (d, 1H, J = 7.0 Hz), 8.47 (s, 1H), 7.75 (s, 1H), 7.68 (d, 1H, J = 9.0 Hz), 7.50 (d, 2H, J = 7.2 Hz), 7.22-7.39 (m, 9H), 6.78 (dd, 1H, J = 7.0, 7.0 Hz), 6.19 (br, 1H), 5.53 (br, 1H), 5.41 (s, 2H), 1.71 (d, 3H, J = 7.0 Hz) .LC / MS: T = 2.05, m / z = 446 (M + H) ⁺ .

Example 121
2-Imidazo [1,2-a] pyridin-3-yl-N- (1-phenylethyl) pyrimidin-4-amine

(1) 2-Chloro-N- (1-phenylethyl) pyrimidin-4-amine Synthesized from 2,4-dichloropyrimidine and DL-1-phenylethylamine in the same manner as in Example 110- (2).
LC / MS: T = 2.03, m / z = 234 (M + H) ⁺ .

(2) 2-Imidazo [1,2-a] pyridin-3-yl-N- (1-phenylethyl) pyrimidin-4-amine In the same manner as in Example 1- (2), 6-bromoimidazo [ Synthesized from 1,2-a] pyridine and 2-chloro-N- (1-phenylethyl) pyrimidin-4-amine.
¹ H-NMR (CDCl ₃ , 300 MHz) δ 9.73 (m, 1H), 8.48 (s, 1H), 8.21 (d, 1H, J = 6.1 Hz), 7.75 (d, 1H, J = 9.0 Hz), 7.26-7.42 (m, 7H), 6.91 (m, 1H), 6.12 (m, 1H), 5.32 (br, 1H), 1.64 (d, 3H, J = 6.8 Hz). LC / MS: T = 1.79, m / z = 316 (M + H) ⁺ .

Examples 122-135
Compounds shown in Tables 8 to 9 in the same manner as in Example 121 using 2,4-dichloro-5-fluoropyrimidine or ethyl 2,4-dichloropyrimidine-5-carboxylate (Reference Example 5) and corresponding raw materials Got.

Example 136
2-Imidazo [1,2-a] pyridin-3-yl-4-[(1-phenylethyl) amino] pyrimidine-5-carboxylic acid

Ethanol solution of ethyl 2-imidazo [1,2-a] pyridin-3-yl-4-[(1-phenylethyl) amino] pyrimidine-5-carboxylate (Example 123) (241 mg, 0.622 mmol) 5N sodium hydroxide aqueous solution (5.0 mL) was added to 5.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, water was added to the obtained residue, and the mixture was washed with ethyl acetate. The aqueous layer was neutralized with 5N aqueous hydrochloric acid, and the resulting solid was collected by filtration to give the title compound (179 mg, 80%).
¹ H-NMR (DMSO, 300 MHz) δ10.20 (br, 1H), 9.52 (d, 1H, J = 7.2 Hz), 8.70 (s, 1H), 8.33 (s, 1H), 7.69 (d, 1H , J = 9.0 Hz), 7.32-7.46 (m, 5H), 7.20 (m, 1H), 7.02 (dd, 1H, J = 6.8, 7.2 Hz), 5.29 (dq, 1H, J = 6.8, 6.8 Hz) , 1.55 (d, 3H, J = 6.8 Hz) .LC / MS: T = 1.89, m / z = 360 (M + H) ⁺ .

Example 137
2-Imidazo [1,2-a] pyridin-3-yl-N-methyl-4-[(1-phenylethyl) amino] pyrimidine-5-carboxamide

2-Imidazo [1,2-a] pyridin-3-yl-4-[(1-phenylethyl) amino] pyrimidine-5-carboxylic acid (Example 136) (25.0 mg, 0.07 mmol) N, To an N-dimethylformamide solution (1.0 mL), an aqueous methylamine solution (50.0 μL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (27.0 mg, 0.140 mmol), 1-hydroxybenzo Triazole hydrate (21.0 mg, 0.140 mmol) and triethylamine (39.0 μL, 0.280 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction system, extracted with chloroform, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 99/1) to obtain the title compound (18.0 mg, 69%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ 9.35 (d, 1H, J = 7.0 Hz), 9.26 (d, 1H, J = 6.8 Hz), 8.48 (s, 1H), 8.47 (s, 1H), 7.66 (d, 1H, J = 9.0 Hz), 7.21-7.45 (m, 6H), 6.78 (dd, 1H, J = 6.8, 7.0 Hz), 6.49 (d, 1H, J = 4.4 Hz), 5.32 (dq , 1H, J = 6.8, 6.8 Hz), 3.03 (d, 3H, J = 4.4 Hz), 1.66 (d, 3H, J = 6.8 Hz). LC / MS: T = 1.93, m / z = 373 (M + H) ⁺ .

Example 138
2-Imidazo [1,2-a] pyridin-3-yl-N, N-dimethyl-4-[(1-phenylethyl) amino] pyrimidine-5-carboxamide

In a manner similar to Example 137, 2-imidazo [1,2-a] pyridin-3-yl-4-[(1-phenylethyl) amino] pyrimidine-5-carboxylic acid (Example 136) and dimethylamine Synthesized from aqueous solution.
¹ H-NMR (CDCl ₃ , 300 MHz) δ 9.40 (d, 1H, J = 7.0 Hz), 8.48 (s, 1H), 8.29 (s, 1H), 7.68 (d, 1H, J = 7.0 Hz), 7.62 (d, 1H, J = 6.8 Hz), 7.22-7.46 (m, 6H), 6.80 (dd, 1H, J = 6.8, 7.0 Hz), 5.32 (dd, 1H, J = 6.8, 6.8 Hz), 3.19 (s, 6H), 1.65 (d, 3H, J = 6.8 Hz) .LC / MS: T = 1.86, m / z = 387 (M + H) ⁺ .

Example 139
4- (2,6-Difluorobenzylamino) -2- (imidazo [1,2-a] pyridin-3-yl) pyrimidine-5-carboxylic acid

The compound was synthesized from the corresponding raw material in the same manner as in Example 136.
¹ H-NMR (DMSO, 400 MHz) δ 13.48 (brs, 1H), 9.90 (d, 1H, J = 6.9 Hz), 9.18 (brs, 1H), 8.80 (s, 1H), 8.52 (s, 1H) , 7.78 (d, 1H, J = 9.0 Hz), 7.54-7.48 (m, 1H), 7.45-7.36 (m, 1H), 7.23-7.11 (m, 3H) 4.94 (d, 2H, J = 6.0 Hz) .

Examples 140-148
In the same manner as in Example 136 or Example 137, the compounds shown in Table 10 were obtained from the corresponding raw materials.

Example 149
2-Imidazo [1,2-a] pyridin-3-yl-5-methyl-N- (1-phenylethyl) pyrimidin-4-amine

(1) 5-Bromo-2-chloro-N- (1-phenylethyl) pyrimidin-4-amine In the same manner as in Example 110- (2), 5-bromo-2,4-dichloropyrimidine and DL- Synthesized from 1-phenylethylamine.
LC / MS: T = 2.31, m / z = 312, 314 (M + H) ⁺ .

(2) 2-Chloro-5-methyl-N- (1-phenylethyl) pyrimidin-4-amine 5-Bromo-2-chloro-N- (1-phenylethyl) pyrimidin-4-amine (110 mg,. 352 mmol) in 1,4-dioxane (3.0 mL), methyl boronic acid (42.0 mg, 0.704 mmol), tris (dibenzylideneacetone) dipalladium (0) (4.80 mg, 0.00528 mmol), -T-Butylphosphonium tetrafluoroborate (4.00 mg, 0.0141 mmol) and cesium carbonate (344 mg, 1.06 mmol) were added, and the mixture was stirred with heating under reflux for 1 hour. The reaction mixture was allowed to cool to room temperature, insoluble matters were filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give the title compound (80.0 mg, 92%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ 7.82 (s, 1H), 7.26-7.40 (m, 5H), 5.45 (dq, 1H, J = 7.0, 6.8 Hz), 4.86 (d, 1H, J = 7.0 Hz), 1.99 (s, 3H), 1.62 (d, 3H, J = 6.8 Hz) .LC / MS: T = 2.13, m / z = 248 (M + H) ⁺ .

(3) 2-Imidazo [1,2-a] pyridin-3-yl-5-methyl-N- (1-phenylethyl) pyrimidin-4-amine In the same manner as in Example 1- (2), 6 -Synthesized from bromoimidazo [1,2-a] pyridine and 2-chloro-5-methyl-N- (1-phenylethyl) pyrimidin-4-amine.
¹ H-NMR (CDCl ₃ , 300 MHz) δ 9.48 (d, 1H, J = 7.0 Hz), 8.40 (s, 1H), 8.08 (s, 1H), 7.65 (d, 1H, J = 9.0 Hz), 7.20-7.45 (m, 6H), 6.78 (dd, 1H, J = 6.8, 7.0 Hz), 5.38 (dq, 1H, J = 6.6, 6.8 Hz), 4.85 (d, 1H, J = 6.6 Hz), 2.14 (s, 3H), 1.67 (d, 3H, J = 6.8 Hz) .LC / MS: T = 1.87, m / z = 330 (M + H) ⁺ .

Examples 150-157
In the same manner as in Example 149, the compounds shown in Table 11 were obtained from the corresponding raw materials.

Example 158
9- (2,6-Difluorobenzyl) -2-imidazo [1,2-a] pyridin-3-yl-7,9-dihydro-8H-purine-8-thione

In Example 1- (4) and the same method, N ⁴ - (2,6-difluorobenzyl) -2-imidazo [1,2-a] pyridin-3-yl-pyrimidin-4,5-diamine (Example 1- (3)) and 1,1′-thiocarbonyldiimidazole.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 9.69 (ddd, 1H, J = 1.1, 1.1, 7.0 Hz), 8.61 (s, 1H), 8.35 (s, 1H), 7.75 (ddd, 1H, J = 1.1, 1.1, 9.0 Hz), 7.41-7.48 (m, 2H), 7.12-7.20 (m, 3H), 5.60 (s, 2H). LC / MS: T = 1.88, m / z = 395 (M + H) ⁺ .

Example 159
9- (2,6-Difluorobenzyl) -2-imidazo [1,2-a] pyridin-3-yl-8- (methylthio) -9H-purine

9- (2,6-difluorobenzyl) -2-imidazo [1,2-a] pyridin-3-yl-7,9-dihydro-8H-purin-8-thione (15.0 mg, 0.0381 mmol, run In Example 158), an N, N-dimethylformamide solution (0.2 mL), 60% sodium hydride (2.0 mg, 0.0500 mmol) and a prepared 0.803 N methyl iodide / N, N-dimethylformamide solution (0.070 mL, 0.0562 mmol) was sequentially added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate-toluene (1: 1). The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 20/1) to obtain the title compound (6.0 mg, 39%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.96 (dd, 1H, J = 1.0, 6.9 Hz), 8.95 (s, 1H), 8.58 (s, 1H), 7.73 (dd, 1H, J = 1.1, 9.0 Hz), 7.30-7.34 (m, 2H), 6.99 (ddd, 1H, J = 1.1, 6.9,
6.9 Hz), 6.94 (dd, 2H, J = 8.1, 8.1 Hz), 5.49 (s, 2H), 2.82 (s, 3H). LC / MS: T = 1.97, m / z = 409 (M + H) ⁺ .

Example 160
9- (2,6-Difluorobenzyl) -N-ethyl-2-imidazo [1,2-a] pyridin-3-yl-9H-purin-8-amine

N ⁴ - (2,6-difluorobenzyl) -2-imidazo [1,2-a] pyridin-3-yl-pyrimidin-4,5-diamine (16.4mg, 0.0467mmol, Example 1- (3) ), Dichloromethane (0.5 mL), ethyl isothiocyanate (0.007 mL, 0.0799 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (28.0 mg, 0.146 mmol) and diisopropyl Ethylamine (0.050 mL, 0.294 mmol) was added, and the mixture was stirred at 110 ° C. for 1 hour under microwave irradiation. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol = 20/1) to give the title compound (4.6 mg, 24%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ 10.06 (d, 1H, J = 7.0 Hz), 8.67 (s, 1H), 8.57 (s, 1H), 7.72 (d, 1H, J = 9.0 Hz), 7.27-7.41 (m, 2H), 6.95-7.03 (m, 3H), 5.34 (s, 2H), 4.91
(br, 1H), 3.61 (dq, 2H, J = 5.4, 7.2 Hz), 1.34 (t, 3H, J = 7.2 Hz). LC / MS: T = 1.84, m / z = 203 (bp), 406 (M + H) ⁺ .

Test Example: JAK3 Inhibition Test The pharmacological activity of the compound of the present invention was confirmed by the following test.
(1) Preparation of human JAK3 As the purified human JAK3 kinase domain, the one attached to QuickScout Screening Assist Kit (Karna Bioscience) was used. This is expressed using a baculovirus expression system in which a His tag is bound to the N-terminus of the fragments 795-1124 (C-terminus) of human JAK3 protein (accession number_000206.2), (41 kDa), Purified using Ni-NTA affinity column chromatography.

(2) Measurement of JAK3 activity JAK3 activity was measured according to the attached protocol using the aforementioned QuickScout Screening Assist Kit. The specific operation was performed as follows.
An assay buffer containing 10 μL of a test compound and 20 μL of an enzyme solution were added to the microplate, stirred well, and incubated at room temperature for 30 minutes. Thereafter, the reaction was started by adding 10 μL of the substrate solution. Biotin-Lyn-peptide and ATP were used as substrates. The solution composition during the reaction was 15 mM Tris-HCl pH 7.5, 0.01% Tween 20, 2 mM DTT,
250 nM Biotin-Lyn-peptide, 5 μM ATP, 20 mM MgCl ₂ .

After incubating at room temperature for 1 hour, the plate was washed 4 times with washing buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.02% Tween 20), and blocking buffer (0.1% Bovine serum albumin was added). Washing buffer containing) was added to the plate. After incubating at room temperature for 30 minutes, the blocking buffer was removed, and an HRP-labeled antibody solution (HRP-labeled antibody diluted 400-fold with blocking buffer) was added. After incubating for 30 minutes at room temperature, the plate was washed 4 times and 100 μL of TMB substrate solution (Pierce, Rockford, IL) was added to the plate. After incubating for 5 minutes at room temperature, 100 μL of 0.1 M sulfuric acid was added to stop the reaction. The enzyme activity was measured as absorbance at 450 nm with a plate reader. The JAK3 inhibitory activity of the test compound was calculated as IC _{50 at} the concentration of the test compound that suppresses JAK3 activity by 50%. Table 12 shows the IC ₅₀ (μM) of the test compound in the JAK3 inhibition test.

  As shown in Table 7, the compounds of the present invention exhibited a strong inhibitory action in the JAK3 inhibition test. Examples 1, 3, 30, 34, 35, 44, 46, 48, 49, 51, 54, 76, 77, 78, 82, 83, 86, 112, 121, 136, 137, 140, 148, 149, Compounds 158 and 159 showed particularly strong inhibitory action.

  As explained above, the nitrogen-containing bicyclic compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is used for rejection in organ transplantation, autoimmune disease, allergic disease, malignant tumor, etc. It can be used as a therapeutic or prophylactic agent.

Claims (15)

The following formula (I):
[Where:
X ¹ represents CR ⁷ or a nitrogen atom,
X ² represents CH or a nitrogen atom,
X ³ and X ⁴ are groups bonded to each other: —X ³ ---- X ⁴ — (wherein the group is —CONR ⁸ —, —CSNR ⁸ —, —C (R ⁹ ) ═N— or — Represents CH = CH-) or
Or X ³ represents a hydrogen atom, and X ⁴ represents a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxycarbonyl, carboxyl, cyano, —NR ¹¹ R ¹² , —CONR ¹¹ R ¹² or —NHCO. It represents a -R ^13,
R ¹ , R ² , R ³ , R ⁴ and R ⁷ are each independently a C _1-6 alkyl which may be substituted with a hydrogen atom, a halogen atom or a fluorine atom, or a fluorine atom. _Represents good C _1-6 alkoxy, C _1-6 alkoxycarbonyl, saturated aliphatic heterocycle, nitro or cyano,
R ⁵ represents a hydrogen atom or —NHR ¹⁰ ;
R ⁶ represents a hydrogen atom, C _1-6 alkyl or R ^{10 ′} ,
R ⁸ is a hydrogen atom; fluorine atom, hydroxyl group, cyano, C _1-6 alkoxycarbonyl, carboxyl, heteroaryl, C _1-6 alkoxy, —NR ¹¹ R ¹² , —CONR ¹¹ R ¹² , saturated aliphatic heterocyclic ring , —NR ¹¹ —saturated aliphatic heterocycle, —O—saturated aliphatic heterocycle, —CO—saturated aliphatic heterocycle, C _1-6 alkanoylamino, aryl, —S (O) _n —C _{1 -6} alkyl, substituted by -SO ₂ NH-C _1-6 alkyl, -NHSO ₂ -C _1-6 alkyl and C _3-8 same or different 1 to 3 groups selected from the group consisting of cycloalkyl An optionally substituted C _1-6 alkyl (wherein the heteroaryl and the group containing a saturated aliphatic heterocyclic ring are a hydroxyl group, a halogen atom, C _1-6 alkoxy, or a C ₁ optionally substituted with fluorine. _-6 alkyl, -CO-C _1-6 alkyl, C _1-6 arco Optionally substituted with 1 to 3 identical or different groups selected from the group consisting of xyloxycarbonyl, —CONR ¹¹ R ¹² , carboxyl and cyano, the aryl is a hydroxyl group, a halogen atom, a C _1-6 alkoxy; , C _1-6 alkyl optionally substituted with fluorine, C _1-6 alkoxycarbonyl, —CONR ¹¹ R ¹² , carboxyl, cyano, and the same or different 1 to Represents a saturated aliphatic heterocyclic ring that may be substituted with C _1-6 alkyl, which may be substituted with three groups;
R ⁹ is a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy, aryl, heteroaryl, —S (O) _n —C _1-6 alkyl, —NHCO—C _1-6 alkyl, or —NR ¹¹ R ¹² represents
R ¹⁰ and R ^{10 ′} are each independently C _3-10 cycloalkyl, saturated aliphatic heterocycle, aryl, heteroaryl, C _3-8 cycloalkyl-C _1-6 alkyl, aryl-C _1-6. Alkyl or heteroaryl-C _1-6 alkyl, wherein each of R ¹⁰ and R ^{10 ′} is a hydroxyl group; a halogen atom; a cyano; a cyano, a hydroxyl group, a fluorine atom, a C _1-6 alkoxycarbonyl, a carboxyl, -CONR ¹¹ R ¹² and C _1-6 identical are selected from the group consisting of alkoxy or different one to three optionally substituted with C _1-6 alkyl; cyano, hydroxyl, fluorine atom, C _{1- 6} alkoxycarbonyl, carboxyl, -CONR ¹¹ R ¹² and C _1-6 same or different one to three C _1-6 alkoxy optionally substituted by groups selected from the group consisting of alkoxy; C _1-6 Alkoxycal Alkylsulfonyl; carboxyl; -S (O) _n -C _1-6 alkyl; -CO-R ¹³ and -CONR ¹¹ be substituted by the same or different 1 to 3 groups selected from the group consisting of R ¹² Often,
R ¹¹ represents a hydrogen atom or C _1-6 alkyl,
R ¹² and R ¹³ are each independently a hydrogen atom or C _1-6 alkyl (wherein the alkyl is a hydroxyl group, cyano, aryl, saturated aliphatic heterocyclic ring, amino, C _1-6 alkylamino and Di (C _1-6 alkyl) amino may be substituted with a group selected from the group consisting of:
n represents 0, 1 or 2;
In the above definition, when X ³ is a hydrogen atom or R ⁵ is —NHR ¹⁰ , X ² is a nitrogen atom]
Or a pharmaceutically acceptable salt thereof. R ⁵ is a hydrogen atom, R ⁶ is R ^{10 ′} , or R ⁵ is —NHR ¹⁰ , and R ⁶ is a hydrogen atom or C _1-6 alkyl.
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. A group in which X ³ and X ⁴ are bonded to each other: —X ³ ——— X ⁴ — (wherein the group is —CONR ⁸ —, —CSNR ⁸ —, —C (R ⁹ ) ═N— or — CH = CH-) or
Or X ³ is a hydrogen atom, and X ⁴ is a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxycarbonyl, carboxyl, cyano, —NR ¹¹ R ¹² , —CONR ¹¹ R ¹² or —NHCO -R ¹³ and R ¹⁰ and R ^{10 '} are each independently C _3-10 cycloalkyl, saturated aliphatic heterocycle, heteroaryl-C _1-6 alkyl, C _3-8 cycloalkyl-C _{1. -6} alkyl or aryl-C _1-6 alkyl, wherein each group of R ¹⁰ and R ^{10 ′} is a hydroxyl group; a halogen atom; a cyano; a cyano, a hydroxyl group, a fluorine atom, a C _1-6 alkoxycarbonyl, carboxyl, -CONR ¹¹ R ¹² and C _1-6 same or different one to three optionally substituted with C _1-6 alkyl is selected from the group consisting of alkoxy, cyano, hydroxyl, fluorine atom, C _1-6 alkoxycarbonyl, potassium C _1-6 alkoxy optionally substituted with 1 to 3 identical or different groups selected from the group consisting of ruxoxyl, —CONR ¹¹ R ¹² and C _1-6 alkoxy; C _1-6 alkoxycarbonyl; carboxyl -S (O) _n -C _1-6 alkyl; optionally substituted by 1 to 3 identical or different groups selected from the group consisting of -CO-R ¹³ and -CONR ¹¹ R ¹² ;
The compound according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof. R ¹⁰ and R ^{10 ′} are each independently C _3-10 cycloalkyl, saturated aliphatic heterocycle, C _3-8 cycloalkyl-C _1-6 alkyl, heteroaryl-C _1-6 alkyl or aryl- C _1-6 alkyl, wherein each of the groups R ¹⁰ and R ^{10 ′} is the same or different from 1 to 3 selected from the group consisting of hydroxyl group; halogen atom; cyano; cyano, hydroxyl group and fluorine atom C _1-6 alkyl optionally substituted with a group of: and C _1-6 alkoxy optionally substituted with 1 to 3 identical or different groups selected from the group consisting of cyano, hydroxyl group and fluorine atom May be substituted with 1 to 3 identical or different groups selected from the group consisting of:
The compound as described in any one of Claims 1-3, or its pharmaceutically acceptable salt. R ⁸ is a hydrogen atom; or hydroxyl group, cyano, C _1-6 alkoxycarbonyl, carboxyl, C _1-6 alkoxy, —NR ¹¹ R ¹² , —CONR ¹¹ R ¹² , a saturated aliphatic heterocycle and —CO—saturated. An aliphatic heterocycle (wherein the saturated aliphatic heterocycle includes a hydroxyl group, C _1-6 alkoxy, —CO—C _1-6 alkyl, C _1-6 alkoxycarbonyl, —CONR ¹¹ R C may be substituted with the same or different 1 to 3 groups selected from the group consisting of ¹² and the same or different 1 to 3 groups selected from the group consisting of carboxyl) _1-6 alkyl,
The compound as described in any one of Claims 1-4, or its pharmaceutically acceptable salt. A group in which X ³ and X ⁴ are bonded to each other: —X ³ ——— X ⁴ — (wherein the group is —CONR ⁸ —, —CSNR ⁸ —, —C (R ⁹ ) ═N— or — CH = CH-).
The compound as described in any one of Claims 1-5, or its pharmaceutically acceptable salt. X ³ is a hydrogen atom, and X ⁴ is a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxycarbonyl, carboxyl or —CONR ¹¹ R ¹² .
The compound as described in any one of Claims 1-5, or its pharmaceutically acceptable salt. X ³ and X ⁴ are a group bonded to each other: —X ³ ——— X ⁴ — (wherein the group is —CONR ⁸ — or —CSNR ⁸ —),
The compound as described in any one of Claims 1-5, or its pharmaceutically acceptable salt. X ³ and X ⁴ are groups bonded to each other: —X ³ ——— X ⁴ — (wherein the group is —C (R ⁹ ) ═N— or —CH═CH—).
The compound as described in any one of Claims 1-5, or its pharmaceutically acceptable salt. X ² is CH,
The compound as described in any one of Claims 1-9, or its pharmaceutically acceptable salt. X ² is a nitrogen atom,
The compound as described in any one of Claims 1-9, or its pharmaceutically acceptable salt. X ¹ is CR ⁷
The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof. R ¹ , R ² , R ³ , R ⁴ and R ⁷ are each a hydrogen atom,
The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.   A therapeutic or prophylactic agent for an autoimmune disease comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient.