JP2021035910A - Substituted purine compound - Google Patents

Abstract

To provide a substituted purine compound useful as a preventive and/or therapeutic agent of autoimmune diseases.SOLUTION: The present application provides a compound represented by formula (1) and a pharmaceutically acceptable salt thereof [In the formula, R1 represents an optionally substituted alkoxy or the like; R2 represents an optionally substituted alkyl or the like; ring Q1 represents an optionally substituted aryl or the like; W1 represents an optionally substituted alkylene or the like; n represents 1- 4; R3 represents H or the like; X1 represents -(CH2)m-O- or the like; m represents 0-2; W2 represents a single bond or the like; R4 represents an optionally substituted 4- to 10-membered saturated hetero ring or the like; X2 represents a single bond or the like; and R5 represents an optionally substituted alkyl, an optionally substituted 4- to 10-membered saturated heterocyclic group, or the like].SELECTED DRAWING: None

Description

The present invention relates to pharmaceutically useful substituted purine derivatives and pharmaceutically acceptable salts thereof, and prophylactic and / or therapeutic agents for autoimmune diseases containing them as active ingredients.

An autoimmune disease is an abnormality in the natural immune system that should play a role in recognizing and eliminating foreign substances such as pathogenic microorganisms that originally invaded from the outside. It is a general term for diseases in which antibodies and autoreactive lymphocytes are constantly overproduced, causing inflammation accompanied by systemic or organ-specific cytokine production, leading to tissue damage.

However, among autoimmune diseases, only a small number of diseases such as rheumatoid arthritis have obtained a sufficient therapeutic effect without serious side effects, and the therapeutic effect and safety. The development of highly sexual therapeutic agents for autoimmune diseases is strongly desired.

In recent years, studies using animal models have revealed that Toll-like receptors (TLRs), especially TLR7, are deeply involved in the pathophysiology of autoimmune diseases (Non-Patent Documents 1 and 2). Therefore, compounds that act on TLRs can be expected to selectively control immune reactions evoked by pathogenic microorganisms, autoantibodies, and autoreactive lymphocytes, and can be expected to be radically treated as new therapeutic agents for autoimmune diseases. .. On the other hand, recent studies using animal models have suggested that the TLR9 inhibitory action may cause diminished drug efficacy and safety problems as a therapeutic agent for autoimmune diseases (Non-Patent Document 3). 4).

As a therapeutic agent for autoimmune diseases having a TLR inhibitory action, for example, chloroquine, hydroxychloroquine and the like are known (Non-Patent Document 5).

Immunity, 2011, 35, 3-5 Arthritis & Rheumatism 2008, 58, 1107-1115 Immunity 2006, 25, 417 ARTHRITIS & RHEUMATOLOGY 2014, 66, 694 European Journal of Immunology, 2004, 34, 2541-2550

The subject of the present invention is the prevention and / or treatment of autoimmune diseases, specifically, diseases involving autoimmune diseases (collagen diseases represented by systemic erythematosus, inflammation, allergies, asthma, graft rejection, graft pair). To provide prophylactic and / or therapeutic agents for host diseases, infectious diseases, cancers), immunodeficiencies, pains or central nervous system diseases (neurodegenerative diseases represented by Alzheimer's disease and Parkinson's disease). Further, by finding a compound that inhibits TLR, particularly TLR7, it is to provide a drug that is particularly effective for the prevention and / or treatment of autoimmune diseases.

As a result of diligent studies, the present inventors have found a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter, may be referred to as "the compound of the present invention"). , It has been found that it exhibits a strong TLR7 inhibitory action and is very useful for the prevention and / or treatment of autoimmune diseases, and has completed the present invention.

That is, the present invention is as follows.

［式中、Ｒ^１は、置換されていてもよいＣ_１−６アルコキシ、置換されていてもよいＣ_３−７シクロアルコキシ、置換されていてもよい４員〜７員の飽和ヘテロ環基−オキシ、置換されていてもよいＣ_１−６アルキル、置換されていてもよいＣ_３−７シクロアルキル、置換されていてもよいＣ_１−６アルキルチオ、置換されていてもよい４員〜７員の飽和ヘテロ環基、置換されていてもよいアミノ、またはハロゲン原子を表し；
Ｒ^２は、置換されていてもよいＣ_１−６アルキル、置換されていてもよいＣ_３−７シクロアルキル、または置換されていてもよいアミノを表し；
Ｗ^１は、単結合、または置換されていてもよいＣ_１−４アルキレンを表し；
環Ｑ^１は、Ｃ_６−１０アリール、または５員〜１０員のヘテロアリールを表し；
ｎは、１、２、３または４を表し；
Ｒ^３は、複数ある場合はそれぞれ独立して、水素原子、ハロゲン原子、シアノ、ヒドロキシ、置換されていてもよいＣ_１−６アルキル、置換されていてもよいＣ_１−６アルコキシ、置換されていてもよいＣ_３−７シクロアルキル、置換されていてもよいＣ_３−７シクロアルコキシ、または置換されていてもよいアミノを表し；
Ｑ^１−Ｘ^１は、Ｑ^１−単結合、Ｑ^１−（ＣＨ_２）_ｍ−Ｏ−、Ｑ^１−（ＣＨ_２）_ｍ−Ｓ−、Ｑ^１−（ＣＨ_２）_ｍ−Ｓ（Ｏ）_２−、Ｑ^１−（ＣＨ_２）_ｍ−ＮＲ^ａＳ（Ｏ）_２−、Ｑ^１−（ＣＨ_２）_ｍ−Ｓ（Ｏ）_２ＮＲ^ａ−、Ｑ^１−（ＣＨ_２）_ｍ−Ｃ（Ｏ）−、Ｑ^１−（ＣＨ_２）_ｍ−ＮＲ^ａ−、Ｑ^１−（ＣＨ_２）_ｍ−ＮＲ^ａＣ（Ｏ）−、またはＱ^１−（ＣＨ_２）_ｍ−Ｃ（Ｏ）ＮＲ^ａ−（ここにおいて、Ｒ^ａは、水素原子またはＣ_１−６アルキルを表し；ｍは、０、１または２を表す）を表し；
Ｗ^２は、単結合、または置換されていてもよいＣ_１−８アルキレンを表し；
Ｒ^４は、−ＯＲ^ｂ（ここにおいて、Ｒ^ｂは、水素原子、置換されていてもよいＣ_１−６アルキル、置換されていてもよいＣ_１−６アルキルカルボニル、置換されていてもよいアミノカルボニル、または置換されていてもよいＣ_１−６アルキルスルホニルを表す）、−ＮＲ^ｃＲ^ｄ（ここにおいて、Ｒ^ｃは、水素原子または置換されていてもよいＣ_１−６アルキルを表し；Ｒ^ｄは、水素原子、置換されていてもよいＣ_１−６アルキル、置換されていてもよいＣ_１−６アルキルカルボニル、置換されていてもよいＣ_１−６アルコキシカルボニル、または置換されていてもよいＣ_１−６アルキルスルホニルを表す）、または置換されていてもよい４員〜１０員の飽和ヘテロ環基を表し；
Ｘ^２−Ｒ^５は、単結合−Ｒ^５、−（ＣＨ_２）_ｋ−Ｃ（Ｏ）−Ｒ^５、または−（ＣＨ_２）_ｋ−Ｃ（Ｏ）ＮＲ^ｅ−Ｒ^５（ここにおいて、Ｒ^ｅは、水素原子または置換されていてもよいＣ_１−６アルキルを表し；ｋは、０、１または２を表す）を表し；
Ｒ^５は、置換されていてもよいＣ_１−６アルコキシ、置換されていてもよいＣ_１−８アルキル、置換されていてもよいＣ_３−１２シクロアルキル、置換されていてもよいＣ_３−７シクロアルコキシ、置換されていてもよいＣ_６−１０アリール、置換されていてもよい４員〜１０員の飽和ヘテロ環基、または置換されていてもよい５員〜１０員のヘテロアリールを表す、ただし、Ｒ^５が置換されていてもよいＣ_６−１０アリールまたは置換されていてもよい５員〜１０員のヘテロアリールであるとき、Ｘ^２−Ｒ^５は単結合−Ｒ^５ではない]で表される化合物、またはその製薬学的に許容される塩。 [1] Equation (1):

[In the formula, R ¹ is _{optionally substituted C 1-6} alkoxy, optionally substituted C _3-7 cycloalkoxy, optionally substituted 4- to 7-membered saturated heterocyclic group- oxy, optionally substituted C _1-6 alkyl, optionally substituted C _3-7 cycloalkyl, optionally substituted C _1-6 alkylthio, 4 may be substituted 7-membered Represents a saturated heterocyclic group, optionally substituted amino, or halogen atom;
R ² represents _{an optionally substituted C 1-6} alkyl, _{an optionally substituted C 3-7} cycloalkyl, or an optionally substituted amino;
W ¹ represents a _{C 1-4} alkylene that may be single bond or substituted;
Ring ^{Q 1} is _represents a _{C 6-10} aryl or a 5- to 10-membered heteroaryl;
n represents 1, 2, 3 or 4;
If there are a plurality of R ³ , hydrogen atom, halogen atom, cyano, hydroxy, C _1-6 alkyl which may be _{substituted, C 1-6} alkoxy which may be substituted, and substituted. also represent an optionally C _3-7 cycloalkyl, optionally substituted C _3-7 cycloalkoxy, or amino which may be substituted;
Q ^1- X ¹ is Q ¹ -single bond, Q ^1- (CH ₂ ) _m- O-, Q ^1- (CH ₂ ) _m -S-, Q ^1- (CH ₂ ) _m- S (O) ₂ −, Q ¹ − (CH ₂ ) _m −NR ^a S (O) ₂ −, Q ¹ − (CH ₂ ) _m − S (O) ₂ NR ^a −, Q ¹ − (CH ₂ ) _m −C ( O) −, Q ¹ − (CH ₂ ) _m −NR ^a −, Q ¹ − (CH ₂ ) _m −NR ^a C (O) −, or Q ¹ − (CH ₂ ) _{m −} C (O) NR ^a -(Here, ^Ra represents a hydrogen atom or C _1-6 alkyl; m represents 0, 1 or 2);
W ² represents a _{C 1-8} alkylene that may be single bonded or substituted;
R ⁴ is −OR ^b (where R ^b is a hydrogen atom, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkyl carbonyl, optionally substituted amino. Carbonyl, or optionally substituted C _1-6 alkyl sulfonyl), -NR ^c R ^d (where R ^c represents hydrogen atom or optionally substituted C _1-6 alkyl; R ^d is a hydrogen atom, an optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkylcarbonyl, optionally substituted C _1-6 alkoxycarbonyl, or optionally substituted Represents a good C _1-6 alkylsulfonyl), or represents a 4- to 10-membered saturated heterocyclic group that may be substituted;
X ^2- R ⁵ is a single bond -R ⁵ ,-(CH ₂ ) _k- C (O) -R ⁵ , or-(CH ₂ ) _k- C (O) NR ^e- R ⁵ (here, R). ^e represents a hydrogen atom or a optionally substituted C _1-6 alkyl; k represents 0, 1 or 2);
R ⁵ may be _{substituted C 1-6} alkoxy, optionally substituted C _1-8 alkyl, _{optionally substituted C 3-12} cycloalkyl, _{optionally substituted C 3- Represents 7} cycloalkoxy, optionally substituted C _6-10 aryl, optionally substituted 4- to 10-membered saturated heterocyclic group, or optionally substituted 5- to 10-membered heteroaryl. However, when R ⁵ is a _{optionally substituted C 6-10} aryl or an optionally substituted 5- to 10-membered heteroaryl, X ^2- R ⁵ is not a single bond-R ⁵ ]. A compound represented by, or a pharmaceutically acceptable salt thereof.

[2] R ¹
(1) C _1-6 Alkoxy, (the group is
(A) Halogen atom,
(B) Hydroxy,
(C) C _1-6 alkoxy (the group may be substituted with the same or different 1-3 halogen atoms),
(D) C _3-7 cycloalkyl (the group is substituted with 1 to 4 similar or heterologous groups selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(E) C _3-7 cycloalkoxy (the group is substituted with 1 to 4 similar or heterologous groups selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(F) Phenyl (the group may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy),}
(G) 5- or 6-membered heteroaryl (the group is substituted with 1 to 4 groups of the same or different species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} (May be), and (h) a 4- to 7-membered saturated heterocyclic group of the same species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} It may be substituted with 1 to 4 different groups)
It may be substituted with 1-3 groups of the same or different species selected from the group consisting of),
(2) C _3-7 cycloalkoxy, (the group is substituted with 1 to 4 groups of the same or different type selected from the group consisting of halogen atom, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(3) 4- to 7-membered saturated heterocyclic group-oxy (the group is 1 to 4 of the same or different species selected from the group _{consisting of halogen atom, C 1-6} alkyl, and C _{1-6 alkoxy.} May be replaced with a group of),
(4) C _1-6 alkyl (the group may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy),}
(5) C _3-7 cycloalkyl (the group is substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(6) C _1-6 alkylthio (the group may be substituted with the same or different 1 to 3 halogen atoms),
(7) 4- to 7-membered saturated heterocyclic groups (the groups are 1 to 4 groups of the same or different species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} May be replaced with),
(8) Amino (the group may be substituted with the same or different 1-2 C _1-6 alkyls (the group may be substituted with the same or different 1-3 halogen atoms). May be), or (9) a halogen atom;
R ² _{is, C 1-6} alkyl (said group may be substituted by same or different 1 to 3 halogen _{atoms), C 3-7} cycloalkyl or amino (in which, is identical or different It may be substituted with 1-2 C _{1-6 alkyls);}
W ¹ is a single bond or _{C 1-4} alkylene (said groups, halogen atoms, hydroxy, and _{C 1-6} optionally substituted with 1-4 groups of same or different selected from the group consisting of alkoxy May be);
Ring ^{Q 1} is _located at _{C 6-10} aryl or a 5- to 10-membered heteroaryl;
n is 1, 2, 3 or 4;
R ³ is, if there are a plurality of independently,
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) With C _1-6 alkyl (the group may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy).} May have been replaced),
(6) C _1-6 alkoxy (the group may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy),}
(7) C _3-7 cycloalkyl (the group is substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(8) C _3-7 cycloalkoxy (the group is substituted with 1 to 4 groups of the same or different type selected from the group consisting of halogen atom, C _1-6 alkyl, and C _{1-6 alkoxy.} (May be), or (9) amino (the group may be substituted with the same or different 1-2 C _1-6 alkyl (the group may be substituted with the same or different 1-3 halogen atoms). ) May be replaced);
Q ¹ -X ¹ - is, ^{Q 1} - single bond _{^{-, Q 1 - (CH 2}} ) m -O-, Q 1 - (CH 2) m -S-, Q 1 - (CH 2) m -S ( O) ₂ −, Q ¹ − (CH ₂ ) _m −NR ^a S (O) ₂ −, Q ¹ − (CH ₂ ) _m − S (O) ₂ NR ^a −, Q ¹ − (CH ₂ ) _m − C (O)-, Q ^1- (CH ₂ ) _m- NR ^a- , Q ^1- (CH ₂ ) _m- NR ^a C (O)-, or Q ^1- (CH ₂ ) _m- C (O) NR ^a − (where ^Ra is a hydrogen atom or C _1-6 alkyl; m is 0, 1 or 2);
W ² represents a _{C 1-8} alkylene that may be single bonded or substituted;
R ⁴
(1) -OR ^b (where R ^b is a hydrogen atom, C _1-6 alkyl, C _1-6 alkyl carbonyl, mono- or di-C _1-6 alkyl-aminocarbonyl, or C _1-6 alkyl (Sulfonyl),
(2) -NR ^c R ^d (where R ^c is a hydrogen atom or C _1-6 alkyl (the group may be substituted with the same or different 1-3 halogen atoms); R ^d is a hydrogen atom, C _1-6 alkyl (the group may be a halogen atom, hydroxy, amino (the group may be substituted with _{one or two C 1-6 alkyls of the same or different),} And C _1-6 alkylcarbonyl (which may be substituted with 1-3 groups of the same or different species selected from the group consisting of _{C 1-6 alkoxy), C 1-6} alkylcarbonyl (where the groups are halogen atoms, hydroxy, amino ( The groups may be substituted with the same or different 1-2 C _1-6 alkyls), and 1-3 groups of the same or different species selected from the group consisting of _{C 1-6 alkoxy.} (May be substituted), C _1-6 alkoxycarbonyl, or C _1-6 alkylsulfonyl), or (3) 4- or 10-membered saturated heterocyclic groups (the groups are:
(A) Halogen atom,
(B) Hydroxy,
(C) Cyano,
(D) C _1-6 alkyl (the group may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy),}
(E) C _1-6 alkoxy (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy),}
(F) C _3-7 cycloalkyl,
(G) C _1-6 alkylcarbonyl (the group may be substituted with a halogen atom, hydroxy, amino (the group may be substituted with the same or different 1-2 C _1-6 alkyls), and C ₁ It may be substituted with 1-3 groups of the same or different species selected from the group consisting of _{-6 alkoxy),}
(H) C _1-6 alkoxycarbonyl,
(I) 4- to 7-membered saturated heterocyclic groups (the groups are 1 to 4 homologous or heterologous groups selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} May be replaced with),
(J) Phenyl (the group may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy),.}
(K) 5- or 6-membered heteroaryl (the group is substituted with 1 to 4 groups of the same or different species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} It may be), and (l) it may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of oxo);
X ^2- R ⁵ is a single bond -R ⁵ ,-(CH ₂ ) _k- C (O) -R ⁵ ,-(CH ₂ ) _k- C (O) NR ^e- R ⁵ (here, ^Re Represents a hydrogen atom or C _1-6 alkyl (the group may be substituted with the same or different 1-3 halogen atoms), or ^Re and R ⁵ are alkyl at the same time. when, saturated Hajime Tamaki (in which the 4-membered to 7-membered together with the nitrogen atom to which R ^e and R ⁵ are attached may be homologous are selected from halogen atoms, and the group consisting of C _1-6 alkyl, or It may be substituted with 1-3 different groups); k represents 0, 1 or 2);
R ⁵
(1) C _1-6 alkoxy, (the group may be substituted with the same or different 1 to 3 halogen atoms).
(2) C _1-8 alkyl (the group is
(A) Halogen atom,
(B) Cyano (c) Hydroxy,
(D) C _1-6 alkoxy (the group may be substituted with the same or different 1-3 halogen atoms),
(E) C _3-7 cycloalkyl (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(F) C _3-7 cycloalkoxy (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(G) Amino (the group is a C _1-6 alkyl (the group is a homologous or heterologous 1-3 group selected from the group consisting of a halogen atom, a cyano, a hydroxy, and a C _{3-7 cycloalkyl). (May} be substituted with), C 3-7 cycloalkyl, C _1-6 alkyl sulfonyl, and C _1-6 alkyl carbonyl substituted with 1 to 4 groups of the same or different species selected from the group. May be),
(H) C _1-6 alkylsulfonyl (the group may be substituted with the same or different 1-3 halogen atoms),
(I) C _6-10 aryl (the groups are halogen atoms, cyano, hydroxy, amino, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, and C _1- It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of _{6 alkylsulfonyls),}
(J) 5- or 6-membered heteroaryl (the groups are halogen atoms, cyanos, C _1-6 alkyls, C _1-6 alcohols, mono- or di-C _1-6 alkylaminos, and C _1-6. It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of alkylsulfonyls), and (k) 4- to 7-membered saturated heterocyclic groups (where the groups are halogen atoms, Cyan, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, C _1-6 alkyl sulfonyl, C _1-6 alkyl carbonyl, and mono- or di-C _{1 It} may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of -6 alkylaminocarbonyl).
It may be substituted with 1-3 groups of the same or different species selected from the group consisting of),
(3) C _3-12 cycloalkyl (the group is halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, C _1-6 alkyl It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of sulfonyls and mono- or di-C _{1-6 alkylaminocarbonyls),}
(4) C _3-7 cycloalkoxy (the group is 1 to 4 groups of the same type or different from each other selected from the group consisting of halogen atom, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with)
(5) C _6-10 aryl (the groups are halogen atoms, cyano, hydroxy, amino, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, and C _1- It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of _{6 alkylsulfonyls),}
(6) 4-membered to 10-membered saturated heterocyclic group (the group is a halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkylamino, C. _It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1-6 alkylsulfonyl, C _1-6 alkylcarbonyl, and mono- or di-C _{1-6 alkylaminocarbonyl.} ), Or (7) 5- to 10-membered heteroaryl (the groups are halogen atoms, cyanos, C _1-6 alkyls, C _1-6 alcohols, mono- or di-C _1-6 alkylaminos, and C. It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of _{1-6 alkylsulfonyls).}
However, when R ⁵ is a _{optionally substituted C 6-10} aryl or an optionally substituted 5- to 10-membered heteroaryl, X ^2- R ⁵ is not a single bond-R ^5.
The compound according to [1] or a pharmaceutically acceptable salt thereof.

[3] R ¹
(1) C _1-6 Alkoxy, (the group is
(A) Halogen atom,
(B) Hydroxy,
(C) C _1-6 alkoxy (the group may be substituted with the same or different 1-3 halogen atoms),
(D) C _3-7 cycloalkyl (the group is substituted with 1 to 4 similar or heterologous groups selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(E) C _3-7 cycloalkoxy (the group is substituted with 1 to 4 similar or heterologous groups selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(F) Phenyl (the group may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy),}
(G) 5- or 6-membered heteroaryl (the group is substituted with 1 to 4 groups of the same or different species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} (May be), and (h) a 4- to 7-membered saturated heterocyclic group of the same species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} It may be substituted with 1 to 4 different groups)
It may be substituted with 1-3 groups of the same or different species selected from the group consisting of),
(2) C _3-7 cycloalkoxy (the group is substituted with 1 to 4 groups of the same or different type selected from the group consisting of halogen atom, C _1-6 alkyl, and C _{1-6 alkoxy.} (May be), or (3) a 4-membered to 7-membered saturated heterocyclic group-oxy (the group is of the same species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy).} The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, which may be substituted with 1 to 4 different groups).

[4] R ¹
(1) C _1-6 alkoxy (the group is the same species selected from the group consisting of halogen atom, hydroxy, C _1-6 alkoxy, C _3-7 cycloalkyl, and 4- to 7-membered saturated heterocyclic groups. Alternatively, it may be substituted with 1 to 3 different groups), or (2) a 4- to 10-membered saturated heterocyclic group-oxy (the group consists of a halogen atom and a C _1-6 alkyl). The compound according to any one of [1] to [3], which may be substituted with 1 to 4 groups of the same type or different types selected from the group, or pharmaceutically acceptable thereof. Salt.

[5] R ² is C _1-6 alkyl (the group may be substituted with the same or different 1-3 halogen atoms), C _3-7 cycloalkyl, or amino, [1]. ] To the compound according to any one of [4] or a pharmaceutically acceptable salt thereof.

[6] The compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof, wherein ^{R 2} _{is C 1-6 alkyl or amino.}

[7] The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof, wherein ^{W 1} _{is C 1-4 alkylene.}

[8] ring Q ¹ is a benzene ring or a 5- or 6-membered aromatic heterocyclic group, [1] A compound or a pharmaceutically acceptable according to any one of to [7] Salt to be done.

[9] The compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

[10] is R ^3, and each independently when a plurality of a hydrogen atom, a halogen atom, hydroxy, C _1-6 alkyl (said group, optionally substituted by the same or different 1 to 3 halogen atoms (Good), or C _1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms), according to any one of [1] to [9]. A compound or a pharmaceutically acceptable salt thereof.

[11] Q ^1- X ¹ is Q ¹ -single bond, Q ^1- (CH ₂ ) _m- O-, Q ^1- (CH ₂ ) _m- C (O)-, Q ^1- (CH ₂ ) _m −NR ^a −, or Q ¹ − (CH ₂ ) _{m −} C (O) NR ^a − (where ^Ra is a hydrogen atom or C _1-6 alkyl; m is 0, 1 or 2 The compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof.

[12] The compound according to any one of [1] to [11] or a pharmaceutically acceptable salt thereof ^{, wherein W 2} is a single bond or C _{1-8 alkylene.}

[13] R ⁴ is,
(1) -OR ^b (where R ^b represents C _1-6 alkyl or C _1-6 alkyl sulfonyl),
(2) -NR ^c R ^d (where R ^c and R ^d are independently substituted with a hydrogen atom or a C _1-6 alkyl (the group is substituted with the same or different 1 to 3 halogen atoms, respectively). (May be), or (3) a 4-membered to 10-membered saturated heterocyclic group (the group is
(A) Halogen atom,
(B) Hydroxy,
(C) C _1-6 alkyl (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy),}
(D) C _1-6 alkoxy (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy),}
(E) C _3-7 cycloalkyl,
(F) C _1-6 alkylcarbonyl (the group may be substituted with a halogen atom, hydroxy, amino (the group may be substituted with the same or different 1-2 C _1-6 alkyls), and C ₁ It may be substituted with 1-3 groups of the same or different species selected from the group consisting of _{-6 alkoxy),}
(G) C _1-6 Alkoxycarbonyl,
(H) 4- to 7-membered saturated heterocyclic group (the group is 1 to 4 homologous or heterologous groups selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} (It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of oxo)), [1] to [12]. The compound according to any one item or a pharmaceutically acceptable salt thereof.

[14] X ^2- R ⁵ is a single bond -R ⁵ or-(CH ₂ ) _k- C (O) -R ⁵ (where j represents 1 or 2; k is 0, 1 Or 2), the compound according to any one of [1] to [13] or a pharmaceutically acceptable salt thereof.

[15] R ⁵ is,
(1) C _1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms),
(2) C _1-8 alkyl, (the group is
(A) Halogen atom,
(B) Cyano (c) Hydroxy,
(D) C _1-6 alkoxy (the group may be substituted with the same or different 1-3 halogen atoms),
(E) C _3-7 cycloalkyl (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(F) C _3-7 cycloalkoxy (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(G) Amino (the group is a C _1-6 alkyl (the group is a homologous or heterologous 1-3 group selected from the group consisting of a halogen atom, a cyano, a hydroxy, and a C _{3-7 cycloalkyl). (May} be substituted with), C 3-7 cycloalkyl, C _1-6 alkyl sulfonyl, and C _1-6 alkyl carbonyl substituted with 1 to 4 groups of the same or different species selected from the group. May be),
And (h) C _1-6 alkylsulfonyl (the group may be substituted with the same or different 1-3 halogen atoms).
It may be substituted with 1-3 groups of the same or different species selected from the group consisting of),
(3) C _3-12 cycloalkyl (the group is halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, C _1-6 alkyl It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of sulfonyls and mono- or di-C _{1-6 alkylaminocarbonyls),}
(4) C _3-7 cycloalkoxy (the group is 1 to 4 groups of the same type or different from each other selected from the group consisting of halogen atom, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with)
(5) C _6-10 aryl (the groups are halogen atoms, cyano, hydroxy, amino, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, and C _1- It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of _{6 alkylsulfonyls),}
(6) 4-membered to 10-membered saturated heterocyclic group (the group is a halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, C. _It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1-6 alkylsulfonyl, C _1-6 alkylcarbonyl, and mono- or di-C _{1-6 alkylaminocarbonyl.} ), Or (7) 5- to 10-membered heteroaryl (the groups are halogen atoms, cyanos, C _1-6 alkyls, C _1-6 alcohols, mono- or di-C _1-6 alkylaminos, and C. _It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1-6 alkylsulfonyls)
The compound according to any one of [1] to [13] or a pharmaceutically acceptable salt thereof.

［式中、Ｒ^１１は、
（１）Ｃ_１−６アルコキシ（該基は、ハロゲン原子、ヒドロキシ、Ｃ_１−６アルコキシ、Ｃ_３−７シクロアルキルおよび４員〜７員の飽和ヘテロ環基からなる群から選択される同種または異種の１〜３個の基で置換されていてもよい）、
（２）４員〜１０員の飽和ヘテロ環基−オキシ（該基は、ハロゲン原子、およびＣ_１−６アルキルからなる群から選択される同種または異種の１〜４個の基で置換されていてもよい）を表し；
Ｒ^１２は、Ｃ_１−６アルキル、またはアミノを表し；
環Ｑ^１１は、ベンゼン環基、または５員もしくは６員の芳香族ヘテロ環基を表し；
Ｒ^１３は、複数ある場合はそれぞれ独立して、
（１）水素原子、
（２）ハロゲン原子、
（３）ヒドロキシ、
（４）Ｃ_１−６アルキル（該基は、同一または異なる１〜３個のハロゲン原子で置換されていてもよい）、または
（５）Ｃ_１−６アルコキシ（該基は、同一または異なる１〜３個のハロゲン原子で置換されていてもよい）を表し；
Ｑ^１１−Ｘ^１１−は、Ｑ^１１−単結合−、Ｑ^１１−（ＣＨ_２）_ｍ−Ｏ−、Ｑ^１１−（ＣＨ_２）_ｍ−Ｃ（Ｏ）−、Ｑ^１１−（ＣＨ_２）_ｍ−ＮＲ^ａ−、またはＱ^１１−（ＣＨ_２）_ｍ−Ｃ（Ｏ）ＮＲ^ａ−（ここにおいて、Ｒ^ａは、水素原子またはＣ_１−６アルキルを表し；ｍは、０、１または２を表す）表し；
Ｗ^１２は、単結合またはＣ_１−３アルキレンを表し；
Ｒ^１４は、
（１）−ＯＲ^ｂ（ここにおいて、Ｒ^ｂは、Ｃ_１−６アルキル、またはＣ_１−６アルキルスルホニルを表す）、
（２）−ＮＲ^ｃＲ^ｄ（ここにおいて、Ｒ^ｃおよびＲ^ｄは、各々独立して、水素原子またはＣ_１−６アルキル（該基は、同一または異なる１〜３個のハロゲン原子で置換されていてもよい）を表す）、
（３）４員〜１０員の飽和ヘテロ環基（該基は、
（ａ）ハロゲン原子、
（ｂ）ヒドロキシ、
（ｃ）Ｃ_１−６アルキル（該基は、ハロゲン原子、ヒドロキシ、およびＣ_１−６アルコキシからなる群から選択される同種または異種の１〜３個の基で置換されていてもよい）、
（ｄ）Ｃ_１−６アルコキシ（該基は、ハロゲン原子、ヒドロキシ、およびＣ_１−６アルコキシからなる群から選択される同種または異種の１〜３個の基で置換されていてもよい）、
（ｅ）Ｃ_３−７シクロアルキル、
（ｆ）Ｃ_１−６アルキルカルボニル（該基は、ハロゲン原子、ヒドロキシ、アミノ（該基は、同一または異なる１〜２個のＣ_１−６アルキルで置換されていてもよい）、およびＣ_１−６アルコキシからなる群から選択される同種または異種の１〜３個の基で置換されていてもよい）、
（ｇ）Ｃ_１−６アルコキシカルボニル、
（ｈ）４員〜７員の飽和ヘテロ環基（該基は、ハロゲン原子、Ｃ_１−６アルキル、およびＣ_１−６アルコキシからなる群から選択される同種または異種の１〜４個の基で置換されていてもよい）、および
（ｉ）オキソ
からなる群から選択される同種または異種の１〜４個の基で置換されていてもよい）を表し；
Ｘ^１２−Ｒ^１５は、単結合、または−（ＣＨ_２）_ｋ−Ｃ（Ｏ）−Ｒ^１５（ここにおいて、ｋは、０、１または２を表す）を表し；
Ｒ^１５は、
（１）Ｃ_１−６アルコキシ（該基は、同一または異なる１〜３個のハロゲン原子で置換されていてもよい）、
（２）Ｃ_１−８アルキル、（該基は、
（ａ）ハロゲン原子、
（ｂ）シアノ
（ｃ）ヒドロキシ、
（ｄ）Ｃ_１−６アルコキシ（該基は、同一または異なる１〜３個のハロゲン原子で置換されていてもよい）、
（ｅ）Ｃ_３−７シクロアルキル（該基は、ハロゲン原子、シアノ、ヒドロキシ、Ｃ_１−６アルキル、およびＣ_１−６アルコキシからなる群から選択される同種または異種の１〜４個の基で置換されていても良い）、
（ｆ）Ｃ_３−７シクロアルコキシ（該基は、ハロゲン原子、シアノ、ヒドロキシ、Ｃ_１−６アルキル、およびＣ_１−６アルコキシからなる群から選択される同種または異種の１〜４個の基で置換されていてもよい）、
（ｇ）アミノ（該基は、Ｃ_１−６アルキル（該基は、ハロゲン原子、シアノ、ヒドロキシ、およびＣ_３−７シクロアルキルからなる群から選択される同種または異種の１〜３個の基で置換されていてもよい）、Ｃ_３−７シクロアルキル、Ｃ_１−６アルキルスルホニル、およびＣ_１−６アルキルカルボニルからなる群から選択される同種または異種の１〜４個の基で置換されていてもよい）
、および
（ｈ）Ｃ_１−６アルキルスルホニル（該基は、同一または異なる１〜３個のハロゲン原子で置換されていてもよい）
からなる群から選択される同種または異種の１〜３個の基で置換されていてもよい）、
（３）Ｃ_３−１２シクロアルキル（該基は、ハロゲン原子、シアノ、ヒドロキシ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、モノ―もしくはジ―Ｃ_１−６アルキルアミノ、Ｃ_１−６アルキルスルホニル、およびモノ―もしくはジ―Ｃ_１−６アルキルアミノカルボニルからなる群から選択される同種または異種の１〜４個の基で置換されていてもよい）、
（４）Ｃ_３−７シクロアルコキシ（該基は、ハロゲン原子、シアノ、ヒドロキシ、Ｃ_１−６アルキル、およびＣ_１−６アルコキシからなる群から選択される同種または異種の１〜４個の基で置換されていてもよい）
（５）Ｃ_６−１０アリール（該基は、ハロゲン原子、シアノ、ヒドロキシ、アミノ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、モノ―もしくはジ―Ｃ_１−６アルキルアミノ、およびＣ_１−６アルキルスルホニルからなる群から選択される同種または異種の１〜４個の基で置換されていてもよい）、
（６）４員〜１０員の飽和ヘテロ環基（該基は、ハロゲン原子、シアノ、ヒドロキシ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、モノ―もしくはジ―Ｃ_１−６アルキルアミノ、Ｃ_１−６アルキルスルホニル、Ｃ_１−６アルキルカルボニル、およびモノ―もしくはジ―Ｃ_１−６アルキルアミノカルボニルからなる群から選択される同種または異種の１〜４個の基で置換されていてもよい）、または
（７）５員〜１０員のヘテロアリール（該基は、ハロゲン原子、シアノ、Ｃ_１−６アルキル、Ｃ_１−６アルコシ、モノ―もしくはジ―Ｃ_１−６アルキルアミノ、Ｃ_１−６アルキルスルホニルからなる群から選択される同種または異種の１〜４個の基で置換されていてもよい）
を表し、ただし、Ｒ^１５が置換されていてもよいＣ_６−１０アリールまたは置換されていてもよい５員〜１０員のヘテロアリールであるとき、Ｘ^１２−Ｒ^１５は単結合−Ｒ^１５ではない]で表される、化合物またはその製薬学的に許容される塩。 [16] Equation (1a):

[In the formula, R ¹¹ is
(1) C _1-6 alkoxy (the group is the same or the same selected from the group consisting of halogen atom, hydroxy, C _1-6 alkoxy, C _{3-7 cycloalkyl and 4- to 7-membered saturated heterocyclic groups.} It may be substituted with 1 to 3 different groups),
(2) 4- to 10-membered saturated heterocyclic group-oxy (the group is substituted with 1 to 4 groups of the same or different species selected from the group consisting of _{halogen atoms and C 1-6 alkyl.} May be);
R ¹² represents C _1-6 alkyl, or amino;
Ring Q ¹¹ represents a benzene ring or a 5- or 6-membered aromatic heterocyclic group;
R ^13, when there are a plurality of independently,
(1) Hydrogen atom,
(2) Halogen atom,
(3) Hydroxy,
(4) C _1-6 alkyl (the group may be substituted with the same or different 1-3 halogen atoms), or (5) C _1-6 alkoxy (the group is the same or different 1). Represents (may be substituted with ~ 3 halogen atoms);
Q ¹¹ -X ¹¹ - ^{is, Q 11} - single bond _{^{-, Q 11 - (CH 2}} ) m -O-, Q 11 - (CH 2) m -C (O) -, Q 11 - (CH 2) m −NR ^a −, or Q ¹¹ − (CH ₂ ) _m −C (O) NR ^a − (where ^Ra represents a hydrogen atom or C _1-6 alkyl; m represents 0, 1 or 2 Represent) Represent;
W ¹² represents a single bond or C _1-3 alkylene;
R ¹⁴ is
(1) -OR ^b (where R ^b represents C _1-6 alkyl or C _1-6 alkyl sulfonyl),
(2) -NR ^c R ^d (where R ^c and R ^d are independently substituted with a hydrogen atom or a C _1-6 alkyl (the group is substituted with the same or different 1 to 3 halogen atoms, respectively). Represents),
(3) 4-membered to 10-membered saturated heterocyclic group (the group is
(A) Halogen atom,
(B) Hydroxy,
(C) C _1-6 alkyl (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy),}
(D) C _1-6 alkoxy (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy),}
(E) C _3-7 cycloalkyl,
(F) C _1-6 alkylcarbonyl (the group may be substituted with a halogen atom, hydroxy, amino (the group may be substituted with the same or different 1-2 C _1-6 alkyls), and C ₁ It may be substituted with 1-3 groups of the same or different species selected from the group consisting of _{-6 alkoxy),}
(G) C _1-6 Alkoxycarbonyl,
(H) A 4- to 7-membered saturated heterocyclic group (the group is a homologous or heterologous 1 to 4 group selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} (May be substituted with 1 to 4 groups of the same or different species selected from the group consisting of oxo));
X ^12- R ¹⁵ represents a single bond, _{or-(CH 2} ) _k- C (O) -R ¹⁵ (where k represents 0, 1 or 2);
R ¹⁵ is,
(1) C _1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms),
(2) C _1-8 alkyl, (the group is
(A) Halogen atom,
(B) Cyano (c) Hydroxy,
(D) C _1-6 alkoxy (the group may be substituted with the same or different 1-3 halogen atoms),
(E) C _3-7 cycloalkyl (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(F) C _3-7 cycloalkoxy (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(G) Amino (the group is a C _1-6 alkyl (the group is a homologous or heterologous 1-3 group selected from the group consisting of halogen atoms, cyanos, hydroxys, and C _{3-7 cycloalkyls). (May} be substituted with), C 3-7 cycloalkyl, C _1-6 alkyl sulfonyl, and C _1-6 alkyl carbonyl substituted with 1 to 4 groups of the same or different species selected from the group. May be)
, And (h) C _1-6 alkylsulfonyl (the group may be substituted with the same or different 1-3 halogen atoms).
It may be substituted with 1-3 groups of the same or different species selected from the group consisting of),
(3) C _3-12 cycloalkyl (the group is halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, C _1-6 alkyl It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of sulfonyls and mono- or di-C _{1-6 alkylaminocarbonyls),}
(4) C _3-7 cycloalkoxy (the group is 1 to 4 groups of the same type or different from each other selected from the group consisting of halogen atom, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with)
(5) C _6-10 aryl (the groups are halogen atoms, cyano, hydroxy, amino, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, and C _1- It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of _{6 alkylsulfonyls),}
(6) 4-membered to 10-membered saturated heterocyclic group (the group is a halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, C. _It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1-6 alkylsulfonyl, C _1-6 alkylcarbonyl, and mono- or di-C _{1-6 alkylaminocarbonyl.} ), Or (7) 5- to 10-membered heteroaryl (the group is a halogen atom, cyano, C _1-6 alkyl, C _1-6 alcohol, mono- or di-C _1-6 alkylamino, C _{1). It} may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of -6 alkylsulfonyl)
However, when R ¹⁵ is a _{optionally substituted C 6-10} aryl or an optionally substituted 5- to 10-membered heteroaryl, X ^12- R ¹⁵ is a single bond-R ¹⁵ . No], a compound or a pharmaceutically acceptable salt thereof.

[17] The compound according to [16] or a pharmaceutically acceptable salt thereof ^{, wherein X 12-} R ¹⁵ is a single bond-R ^15.

[18] R ¹¹ is _{substituted with C 1-6} alkoxy (the group is substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy.} The compound according to [16] or [17] or a pharmaceutically acceptable salt thereof.

[19] R ¹⁴
(1) -NR ^c R ^d (where R ^c and R ^d are independently substituted with a hydrogen atom or a C _1-6 alkyl (the group is substituted with the same or different 1 to 3 halogen atoms, respectively). (May be), or (2) a 4-membered to 10-membered nitrogen-containing saturated heterocyclic group (the group is
(A) Halogen atom,
(B) Hydroxy,
(C) C _1-6 alkyl (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy),}
(D) C _1-6 alkoxy (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy),}
(E) C _3-7 cycloalkyl,
(F) C _1-6 alkylcarbonyl (the group may be substituted with a halogen atom, hydroxy, amino (the group may be substituted with the same or different 1-2 C _1-6 alkyls), and C ₁ It may be substituted with 1-3 groups of the same or different species selected from the group consisting of _{-6 alkoxy),}
(G) C _1-6 Alkoxycarbonyl,
(H) A 4- to 7-membered saturated heterocyclic group (the group is a homologous or heterologous 1 to 4 group selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of (i) oxo).
The compound according to any one of [16] to [18] or a pharmaceutically acceptable salt thereof.

[20] A drug containing the compound according to any one of [1] to [19] or a pharmaceutically acceptable salt thereof as an active ingredient.

[21] A therapeutic agent for an autoimmune disease, which comprises the compound according to any one of [1] to [19] or a pharmaceutically acceptable salt thereof as an active ingredient.

[22] A TLR7 inhibitor containing the compound according to any one of [1] to [19] or a pharmaceutically acceptable salt thereof as an active ingredient.

[23] Systemic lupus erythematosus, lupus nephritis, Sjogren's syndrome, idiopathic thrombocytopenia containing the compound according to any one of [1] to [19] or a pharmaceutically acceptable salt thereof as an active ingredient. A treatment for lupus erythematosus, psoriasis, rheumatoid arthritis, polymyositis, dermatomyositis, Behcet's disease, polysclerosis, or pemphigus.

[24] The compound according to any one of [1] to [19] or a pharmaceutically acceptable salt thereof, a steroid agent, an immunosuppressant, a B cell targeting agent, a TLR inhibitor, and the like. And other drugs selected from therapeutic agents for autoimmune diseases in combination with at least one drug.

[25] Manufactures therapeutic agents for systemic lupus erythematosus, lupus nephritis, Sjogren's syndrome, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, polymyositis, dermatomyositis, Behcet's disease, polysclerosis, or pemphigus. Use of the compound according to any one of [1] to [19] or a pharmaceutically acceptable salt thereof.

[26] Systemic lupus erythematosus, which comprises administering to a mammal an effective amount of the compound according to any one of [1] to [19] or a pharmaceutically acceptable salt thereof. Treatment of lupus nephritis, Sjogren's syndrome, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, polymyositis, dermatomyositis, Behcet's disease, polysclerosis, or pemphigus.

The compound of the present invention exhibits excellent TLR7 inhibitory activity. In addition, in a preferred embodiment of the compound of the present invention, since the bioavailability at the time of oral administration is high, it is useful as a prophylactic and / or therapeutic agent for orally administrable autoimmune diseases. ..

Hereinafter, the present invention will be described in detail. In the present specification, the number of carbons in the definition of "substituent" may be expressed _{as, for example, "C 1-6".} Specifically, the _{notation "C 1-6} alkyl" is synonymous with an alkyl group having 1 to 6 carbon atoms.

Specific examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

"C _1-6 alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferably, it is "C _1-4 alkyl". Specific examples of "C _1-6 alkyl" include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, etc. Examples thereof include 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.

"C _1-8 alkyl" means a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms. It is preferably "C _1-6 alkyl" and more preferably "C _1-4 alkyl". Specific examples of "C _1-8 alkyl" include, for example, heptyl, isoheptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, in addition to the _{above "C 1-6 alkyl".} 1,1-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1-propylpropane, octyl, Isooctyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 1,1-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4, Examples thereof include 4-dimethylhexyl, 5,5-dimethylhexyl, 1-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 1-propylpentyl, 2-propylpentyl and the like.

"C _3-7 cycloalkyl" means a 3- to 7-membered monocyclic saturated or partially unsaturated hydrocarbon group. Preferably, it is "C _3-6 cycloalkyl". Specific examples of "C _3-7 cycloalkyl" include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and the like.

"C _3-12 cycloalkyl" means a 3- to 12-membered monocyclic saturated or partially unsaturated hydrocarbon group. Preferably, it is "C _3-10 cycloalkyl". Specific examples of "C _3-12 cycloalkyl" include, for example, cycloheptyl, cyclooctyl, cycloheptenyl, cyclooctenyl, adamantyl and the like in addition to the above-mentioned "C _{3-7 cycloalkyl".}

"C _1-8 alkylene" is a linear or branched divalent saturated hydrocarbon group having 1 to 8 carbon atoms, or a divalent saturated hydrocarbon group having a cyclic structure having 3 to 8 carbon atoms. It means a hydrocarbon group.
Specific examples of the linear or branched "C _1-8 alkylene" include methylene, ethylene, trimethylene, tetramethylene, 1-methylmethylene, 1-ethylmethylene, 1-propylmethylene and 1-methylethylene. , 2-Methylethylene, 1-ethylethylene and the like, preferably methylene and ethylene.
_{Specific examples of "C 3-8} alkylene" containing a cyclic structure include groups represented by the following groups.

"C _1-4 alkylene" is a linear or branched divalent saturated hydrocarbon group having 1 to 4 carbon atoms, or a divalent saturated hydrocarbon group having a cyclic structure having 3 to 4 carbon atoms. It means a hydrocarbon group.
Specific examples of the _{"C 1-4} alkylene" containing a linear, branched, or cyclic structure include alkylenes having 1 to 4 carbon atoms in _{the above "C 1-8 alkylene".} Be done.

_{"C 1-6} alkyl" moiety of the _{"C 1-6} alkoxy" has the same meaning as the _{"C 1-6} alkyl". Preferably, it is "C _1-4 alkoxy". Specific examples of "C _1-6 alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

_{"C 3-7} cycloalkoxy" is synonymous with _{"C 3-7} cycloalkyloxy", _{"C 3-7} cycloalkyl" moiety is the same as defined in the _{"C 3-7} cycloalkyl". Specific examples of "C _3-7 cycloalkoxy" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

The "C _1-6 alkyl" portion of the "C _1-6 alkyl thio" is synonymous with the _{"C 1-6 alkyl".} Preferably, it is "C _1-4 alkyl thio". Specific examples of "C _1-6 alkylthio" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio and the like.

_{"C 1-6} alkyl" moiety of the _{"C 1-6} alkylcarbonyl" is the same as defined in the _{"C 1-6} alkyl". Preferably, it is "C _1-4 alkylcarbonyl". Specific examples of "C _1-6 alkylcarbonyl" include methylcarbonyl (acetyl), ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, pentylcarbonyl, hexylcarbonyl and the like.

_{"C 1-6} alkoxycarbonyl" is synonymous with _{"C 1-6} alkyloxycarbonyl", _{"C 1-6} alkyl" moiety is the same as defined in the _{"C 1-6} alkyl". Preferably, it is "C _1-4 alkoxycarbonyl". Specific examples of "C _1-6 alkoxycarbonyl" include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like.

The "C _1-6 alkyl" portion of the "mono-or di-C _1-6 alkyl amino" is synonymous with the _{"C 1-6 alkyl".} Preferably, it is "mono- or di-C _1-4 alkylamino". Specific examples of "mono- or di-C _1-6 alkylamino" include, for example, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, butylamino, pentylamino, hexylamino, and methylethylamino. , Methylpropylamino, ethylpropylamino, dipropylamino and the like.

The "C _1-6 alkyl" portion of the "mono-or di-C _1-6 alkyl aminocarbonyl" is synonymous with the _{"C 1-6 alkyl".} Preferably, it is "mono- or di-C _1-4 alkylaminocarbonyl". Specific examples of the "mono- or di-C _1-6 alkylaminocarbonyl" include methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl, and pentyl. Examples thereof include aminocarbonyl, hexylaminocarbonyl, methylethylaminocarbonyl, methylpropylaminocarbonyl, ethylpropylaminocarbonyl, azetidinecarbonyl, pyrrolidinecarbonyl, piperidinecarbonyl and the like.

_{"C 1-6} alkyl" moiety of the _{"C 1-6} alkylsulfonyl" is the same as defined in the _{"C 1-6} alkyl". Preferably, it is "C _1-4 alkyl sulfonyl". Specific examples of the "C _1-6 alkyl sulfonyl" include methyl sulfonyl (mesyl), ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, pentyl sulfonyl, hexyl sulfonyl and the like.

"C _6-10 aryl" means an aromatic hydrocarbon group having 6 to 10 carbon atoms. It is preferably "C ₆ aryl" (phenyl). Specific examples of "C _6-10 aryl" include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.

The "C _6-10 aryl" contains one or more (for example, 1 to 4) heteroatoms (for example, 1 to 4) that are the same or different from phenyl and a hetero atom selected from a 5- to 7-membered nitrogen atom, sulfur atom or oxygen atom. , Or a group fused with a 5- to 7-membered saturated hydrocarbon ring (cyclopentane, or cyclohexane) is also included. _{However, in the case of a polycyclic "C 6-10} aryl group" in which an aromatic ring and a non-aromatic ring are fused, only the aromatic ring has a "group" bond.
Specific examples of the group include groups represented by the following formulas. In the formula below, a bond across a ring means that the "group" is bonded at a substitutable position in the ring.

The _{"C 6-10} aromatic carbocyclic group" in ring ^{Q 1,} refers to an aromatic carbocyclic group having a number 6 to 10 carbons. A benzene ring group (phenylene) is preferable.

The "C _6-10 aromatic carbocyclic group" includes one or more heteroatoms selected from a benzene ring and a 5- to 7-membered nitrogen atom, sulfur atom or oxygen atom (for example, 1 to 4). It also includes a ring containing) or a group fused with a 5- to 7-membered saturated hydrocarbon ring (cyclopentane, cyclohexane, or cycloheptane).
Here, W ¹ is bound only to the aromatic ring. For X ¹ and R ³ , they can be attached at substitutable positions in the aromatic or non-aromatic ring. Specific examples of the group include groups represented by the following formulas.

Examples of the "5-membered to 10-membered heteroaryl" include 5-membered to 10-membered monocyclic or bicyclic aromatic heterocyclic groups, which are nitrogen atom, sulfur atom and oxygen. It contains one or more (for example, 1 to 4) heteroatoms of the same type or different types selected from the atoms. Bicyclic heteroaryl groups also include those in which the monocyclic heteroaryl group is fused with an aromatic ring (benzene, pyridine, etc.) or a non-aromatic ring (cyclohexane, piperidine, etc.). Specific examples of the "heteroaryl group" include a group represented by the following formula.

のヘテロアリールの場合には、２−ピリジル、３-ピリジルまたは４−ピリジルであることを意味する。 A bond across a ring in the equation means that the "group" is attached at a substitutable position in the ring. For example, the following formula

In the case of heteroaryl, it means that it is 2-pyridyl, 3-pyridyl or 4-pyridyl.

で表される場合には、１−ベンゾイミダゾリル、または２−ベンゾイミダゾリルの他に、４−、５−、６−または７−ベンゾイミダゾリルであってもよい。 Further, when "heteroaryl" is a bicyclic group, for example, the following formula

When represented by, in addition to 1-benzoimidazolyl or 2-benzoimidazolyl, 4-, 5-, 6- or 7-benzoimidazolyl may be used.

で表される「多環式のヘテロアリール基」の場合には、「基」が２−、３−、または４−位で結合することを意味する。 However, in the case of a polycyclic heteroaryl group in which an aromatic ring and a non-aromatic ring (cyclohexane, piperidine, etc.) are fused, only the aromatic ring has a "group" bond. For example, the following formula

In the case of a "polycyclic heteroaryl group" represented by, it means that the "group" is bonded at the 2-, 3-, or 4-position.

The "5-membered to 10-membered aromatic heterocyclic group" in ring Q ^1, for example, include a monocyclic or bicyclic aromatic heterocyclic group such as 5- to 10-membered, said group, It contains one or more (for example, 1 to 4) heteroatoms of the same type or different types selected from nitrogen atoms, sulfur atoms and oxygen atoms. The bicyclic aromatic heterocycle also includes a fused ring of the monocyclic aromatic heterocycle and an aromatic ring (benzene, pyridine, etc.) or a non-aromatic ring (cyclohexane, piperidine, etc.).

When the "5- to 10-membered aromatic heterocyclic group" is an aromatic heterocyclic group in which a monocyclic aromatic heterocycle and an aromatic ring or a non-aromatic ring are fused, W ¹ is , Bonds only to aromatic rings. For X ¹ and R ³ , they can be attached at substitutable positions in the aromatic or non-aromatic ring.

The "4-membered to 10-membered saturated heterocyclic group" includes, for example, a 4-membered to 10-membered monocyclic group having 1 to 3 atoms of the same type or different types selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples include a polycyclic saturated heterocyclic group. The nitrogen atom, oxygen atom, and sulfur atom are all atoms constituting a ring. The heterocyclic group may be either saturated or partially unsaturated. It is preferably a saturated heterocyclic group, and more preferably a 5- or 6-membered saturated heterocyclic group. Specifically, pyranyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuryl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, azepanyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, Oxooxazolidyl, dioxooxazolidinyl, dioxothiazolidinyl, 5-oxo-1,2,4-oxadiazole-3-yl, 5-oxo-1,2,4-thiadiazole-3 -Il, 5-thioxo-1,2,4-oxadiazole-3-yl and the like can be mentioned. The bond of the group may be either a carbon atom or a nitrogen atom constituting a ring.

The "4- to 10-membered nitrogen-containing saturated heterocyclic group" includes, for example, 1 to 3 nitrogen atoms and 1 to 2 atoms of the same type or different types arbitrarily selected from oxygen atoms and sulfur atoms. Examples thereof include 4-membered to 10-membered monocyclic or polycyclic saturated heterocyclic groups. The nitrogen atom, oxygen atom, and sulfur atom are all atoms constituting a ring. The ring may be either saturated or partially unsaturated. Specifically, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiadiazole, imidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxooxazolidinyl. Oxothiazolidinyl, 5-oxo-1,2,4-oxadiazole-3-yl, 5-oxo-1,2,4-thiadiazole-3-yl, 5-thioxo-1,2,4- Examples thereof include oxadiazole-3-yl, 1,2,3,6-tetrahydropyridine-4-yl, 2,5-dihydro-1H-pyrrole-3-yl and the like. The bond of the group may be either a carbon atom or a nitrogen atom constituting a ring.

The "4 to 10-membered nitrogen-containing saturated heterocyclic group" includes a saturated bicyclo ring group, a saturated condensed ring group, and a saturated spiro ring group having a "4 to 10-membered nitrogen-containing saturated heterocyclic group" as a basic skeleton. Is also included. Specific examples include "groups" represented by the following groups.

In-(CH ₂ ) _k- C (O) NR ^e- R ⁵ in X ^{2- R 5} , when ^Re and R ⁵ are alkyl at the same time, together with the nitrogen atom to which ^Re and R ^{5 are attached.} As the 4- to 7-membered saturated heterocyclic group formed in, specifically, azetidine, pyrrolidine, piperidine, piperidine, azepan, morpholine, thiomorpholine, dioxothiomorpholine, oxetane, tetrahydrofuran, tetrahydropyran, oxepan. , Dihydrofuran, dihydropyran, tetrahydrooxepine, tetrahydrothiophene dioxide, tetrahydrothiophene dioxide, thiepan dioxide, dihydrothiophene dioxide, dihydrothiopyran dioxide, tetrahydrothiophene dioxide and the like.

"May be substituted C _1-6 alkyl", " _{May be substituted C 1-6} alkoxy", " _{May be substituted C 1-6} alkylthio", "May be substituted C _"1-6 alkylcarbonyl", " _{optionally C 1-6} alkoxycarbonyl", "optionally C _1-6 alkylsulfonyl _{", "optionally C 1-4} alkylene" Examples of the substituent in the above include hydroxy, halogen atom, C _1-6 alkoxy and the like, and preferably halogen atom.

" _Optionally substituted C _3-7 cycloalkyl", "optionally substituted C 3-7 cycloalkoxy", "optionally substituted 4- to 7-membered saturated heterocyclic group", "optional Examples of the substituent in the "optionally substituted 4- to 7-membered saturated heterocyclic group-oxy" include a halogen atom, C _1-6 alkyl, C _1-6 alkoxy and the like.

In "optionally substituted C _6-10 aryl", "optionally substituted 5-membered to 10-membered heteroaryl", "optionally optionally substituted 4-membered to 10-membered saturated heterocyclic group" As the substituent, for example,
(A) Halogen atom,
(B) Cyano,
(C) Hydroxy (d) Amino (e) C _1-6 alkyl (the group is one to three groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy.} May have been replaced),
(F) C _1-6 alkoxy (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy),}
(G) Mono- or di-C _1-6 alkylamino (h) C _1-6 alkylsulfonyl (the group may be substituted with the same or different 1-3 halogen atoms),
(I) Mono- or di-C _1-6 alkylaminocarbonyl, or (j) C _1-6 alkylcarbonyl (the group may be substituted with the same or different 1-3 halogen atoms).
And so on.

Examples of the substituent in the "optionally substituted amino" and the "optionally substituted aminocarbonyl" include C _1-6 alkyl and the like.

In another embodiment, as the substituent in " _{optionally substituted C 1-6} alkoxy", for example,
(A) Halogen atom,
(B) Hydroxy,
(C) C _1-6 alkoxy (the group may be substituted with the same or different 1-3 halogen atoms),
(D) C _3-7 cycloalkyl (the group is substituted with 1 to 4 similar or heterologous groups selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(E) C _3-7 cycloalkoxy (the group is substituted with 1 to 4 similar or heterologous groups selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(F) Phenyl (the group may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy),}
(G) 5- or 6-membered heteroaryl (the group is substituted with 1 to 4 groups of the same or different species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} (May be), or (h) a 4- to 7-membered saturated heterocyclic group, the same or of which is selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} It may be substituted with 1 to 4 different groups)
And so on.

In another embodiment, as the substituent in the "4-membered to 10-membered saturated heterocyclic group", for example,
(A) Halogen atom,
(B) Hydroxy,
(C) Cyano,
(D) C _1-6 alkyl (the group may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy),}
(E) C _1-6 alkoxy (the group is substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be good),
(F) C _3-7 cycloalkyl (the group may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy).} ,
(G) C _1-6 alkylcarbonyl (the group may be substituted with a halogen atom, hydroxy, amino (the group may be substituted with the same or different 1-2 C _1-6 alkyls), and C ₁ It may be substituted with 1-3 groups of the same or different species selected from the group consisting of _{-6 alkoxy),}
(H) C _1-6 alkoxycarbonyl (the group may be substituted with the same or different 1-3 halogen atoms),
(I) 4- to 7-membered saturated heterocyclic groups (the groups are 1 to 4 homologous or heterologous groups selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} May be replaced with),
(J) Phenyl (the group may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy),.}
(K) 5- or 6-membered heteroaryl (the group is substituted with 1 to 4 groups of the same or different species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} (May be), or (l) oxo.

Examples of the substituent in the " _optionally substituted C 1-8 alkyl" include, for example.
(A) Halogen atom,
(B) Cyano (c) Hydroxy,
(D) C _1-6 alkoxy (the group may be substituted with the same or different 1-3 halogen atoms),
(E) C _3-7 cycloalkyl (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(F) C _3-7 cycloalkoxy (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(G) Amino (the group is a C _1-6 alkyl (the group is a homologous or heterologous 1-3 group selected from the group consisting of a halogen atom, a cyano, a hydroxy, and a C _{3-7 cycloalkyl). (May} be substituted with), C 3-7 cycloalkyl, C _1-6 alkyl sulfonyl, and C _1-6 alkyl carbonyl substituted with 1 to 4 groups of the same or different species selected from the group. May be),
(H) C _1-6 alkylsulfonyl (the group may be substituted with the same or different 1-3 halogen atoms),
(I) C _6-10 aryl (the groups are halogen atoms, cyano, hydroxy, amino, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, and C _1- It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of _{6 alkylsulfonyls),}
(J) 5- or 6-membered heteroaryl (the groups are halogen atoms, cyanos, C _1-6 alkyls, C _1-6 alcohols, mono- or di-C _1-6 alkyl aminos, and C _1-6. It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of alkylsulfonyls), or (k) 4- to 7-membered saturated heterocyclic groups (where the groups are halogen atoms, Cyan, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, C _1-6 alkyl sulfonyl, C _1-6 alkyl carbonyl, and mono- or di-C _{1 It} may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of -6 alkylaminocarbonyl).
Can be mentioned.

_{Examples of the substituent in "C 3-12} cycloalkyl which may be substituted" include, for example.
(A) Halogen atom,
(B) Cyano,
(C) Hydroxy,
(D) C _1-6 alkyl (the group may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy),}
(E) C _1-6 alkoxy (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy),}
(F) Mono- or di-C _1-6 alkylamino,
(G) C _1-6 alkylsulfonyl (the group may be substituted with the same or different 1-3 halogen atoms), or (h) mono- or di-C _1-6 alkylaminocarbonyl. Can be mentioned.

Among the compounds of the present invention represented by the formula (1), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W ¹ , W ² , X ¹ , X ² , and ring Q ¹ are preferable. Although as follows, the technical scope of the present invention is not limited to the range of the compounds listed below. Preferred embodiments of the corresponding R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , W ¹² , X ¹¹ , X ¹² , and Ring Q ¹² shall also be in accordance with the following description.

Preferred as R ^1,
(1) C _1-6 Alkoxy (the group is
(A) Halogen atom,
(B) Hydroxy,
(C) C _1-6 alkoxy (the group may be substituted with the same or different 1-3 halogen atoms),
(D) C _3-7 cycloalkyl (the group is substituted with 1 to 4 similar or heterologous groups selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(E) C _3-7 cycloalkoxy (the group is substituted with 1 to 4 similar or heterologous groups selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(F) Phenyl (the group may be substituted with 1 to 4 groups of the same or different dissimilarity selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy),.} (G) 5- or 6-membered heteroaryl (the group is substituted with 1 to 4 homologous or heterologous groups selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} (May be), and (h) a 4- to 7-membered saturated heterocyclic group of the same species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1 to 4 groups of different species),
(2) C _3-7 cycloalkoxy (the group is substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atom, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(3) 4- to 7-membered saturated heterocyclic group-oxy (the group is 1 to 4 of the same or different species selected from the group _{consisting of halogen atom, C 1-6} alkyl, and C _{1-6 alkoxy.} May be replaced with a group of),
Can be mentioned.

More preferably as R ¹ _{, the group consists of C 1-6} alkoxy (the group consists of a halogen atom, hydroxy, C _1-6 alkoxy, C _3-7 cycloalkyl, and a 4- to 7-membered saturated heterocyclic group. It may be substituted with 1 to 3 groups of the same or different species of choice; more preferably from C _1-6 alkoxy, which groups are from halogen atoms, hydroxy, and C _1-6 alkoxy. be made may be substituted with 1-3 groups of same or different selected from the group); more preferably, C _1-6 alkoxy (said group optionally substituted with C _1-6 alkoxy May be good).

R ² preferably _{is, C 1-6} alkyl (said group may be substituted by same or different 1 to 3 halogen _{atoms), C 3-7} cycloalkyl, or amino and the like. It is more preferably C _1-6 alkyl or amino; even _{more preferably C 1-4} alkyl.

Preferred as R ^3,
(1) Hydrogen atom,
(2) Halogen atom,
(3) Hydroxy,
(4) With C _1-6 alkyl (the group may be substituted with 1 to 3 groups of the same or different type selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy).} Substituted), or (6) C _1-6 alkoxy (the group is one to three groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy.} May be replaced with)
Can be mentioned.

More preferably, as R ³ , a hydrogen atom, a halogen atom, a C _1-6 alkyl (the group may be substituted with the same or different 1-3 halogen atoms), or a C _1-6 alkoxy (the group). The group may be substituted with the same or different 1 to 3 halogen atoms).

Preferred as R ^4,
(1) -OR ^b (where R ^b represents C _1-6 alkyl or C _1-6 alkyl sulfonyl),
(2) -NR ^c R ^d (where R ^c and R ^d are hydrogen atoms or C _1-6 alkyl (the groups may be substituted with the same or different 1 to 3 halogen atoms). (Representing), or (3) 4-membered to 10-membered saturated heterocyclic group (the group is
(A) Halogen atom,
(B) Hydroxy,
(C) C _1-6 alkyl (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy),}
(D) C _1-6 alkoxy (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy),}
(E) C _3-7 cycloalkyl,
(F) C _1-6 alkylcarbonyl (the group may be substituted with a halogen atom, hydroxy, amino (the group may be substituted with the same or different 1-2 C _1-6 alkyls), and C ₁ It may be substituted with 1-3 groups of the same or different species selected from the group consisting of _{-6 alkoxy),}
(G) C _1-6 Alkoxycarbonyl,
(H) 4- to 7-membered saturated heterocyclic group (the group is 1 to 4 homologous or heterologous groups selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of (i) oxo).
Can be mentioned.

More preferred as R ^4,
(1) -NR ^c R ^d (where R ^c and R ^d are independently substituted with a hydrogen atom or a C _1-6 alkyl (the group is substituted with the same or different 1 to 3 halogen atoms, respectively). (May be), or (2) a 4-membered to 10-membered nitrogen-containing saturated heterocyclic group (the group is
(A) Halogen atom,
(B) Hydroxy,
(C) C _1-6 alkyl (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy),}
(D) C _1-6 alkoxy (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy),}
(E) C _3-7 cycloalkyl,
(F) C _1-6 alkylcarbonyl (the group may be substituted with a halogen atom, hydroxy, amino (the group may be substituted with the same or different 1-2 C _1-6 alkyls), and C ₁ It may be substituted with 1-3 groups of the same or different species selected from the group consisting of _{-6 alkoxy),}
(G) C _1-6 Alkoxycarbonyl,
(H) may be substituted with 1 to 4 homologous or heterologous groups selected from the group consisting of 4- to 7-membered saturated heterocyclic groups), and (i) selected from the group consisting of oxo. May be substituted with 1 to 4 groups of the same or different species)
Can be mentioned.

More preferably the R ^4, the following formula (2), (3), (4), (5), (6), or (7):

［式中、Ｒ^１６は、Ｃ_１−６アルキル（該基は、ハロゲン原子、ヒドロキシ、およびＣ_１−６アルコキシからなる群から選択される同種または異種の１〜３個の基で置換されていてもよい）、Ｃ_３−７シクロアルキル、Ｃ_１−６アルキルカルボニル、または４員〜７員の飽和ヘテロ環基を表す］で表される基である。

^{Wherein, R 16} _{is C 1-6} alkyl (in which the halogen atom, hydroxy, and _{C 1-6} optionally substituted with 1-3 groups of same or different selected from the group consisting of alkoxy It represents a C _3-7 cycloalkyl, a C _1-6 alkyl carbonyl, or a 4- to 7-membered saturated heterocyclic group].

W ¹ is preferably C _1-4 alkylene; more preferably methylene.

Preferable examples of W ² include a single bond or C _{1-8 alkylene.} More preferably, it is a single bond, or methylene; even more preferably, it is a single bond.

Preferably Q ^1- X ¹ is Q ¹ -single bond, Q ^1- (CH ₂ ) m-O-, Q ^1- (CH ₂ ) m-C (O)-, Q ^1- (CH ₂ ) m. −NR ^a −, or Q ¹ − (CH ₂ ) m − C (O) NR ^a − (where ^Ra represents a hydrogen atom or C _1-6 alkyl; m represents 0, 1 or 2 Represents). More preferably, ^{Q 1} - single bond or _{^{Q 1 - (CH 2) m}} -O- ( wherein, m represents 0 or 1).

Preferably the ring Q ¹ represents an aromatic heterocyclic group of a benzene ring or a 5- or 6-membered.

Preferable examples of X ^2- R ⁵ include single bond −R ⁵ or − (CH ₂ ) _k −C (O) −R ⁵ (where k represents 0, 1 or 2), and more. Preferably, single bond-R ⁵ is mentioned.

Preferably as R ^5,
(1) C _1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms),
(2) C _1-8 alkyl, (the group is
(A) Halogen atom,
(B) Cyano (c) Hydroxy,
(D) C _1-6 alkoxy (the group may be substituted with the same or different 1-3 halogen atoms),
(E) C _3-7 cycloalkyl (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(F) C _3-7 cycloalkoxy (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(G) Amino (the group is a C _1-6 alkyl (the group is a homologous or heterologous 1-3 group selected from the group consisting of halogen atoms, cyanos, hydroxys, and C _{3-7 cycloalkyls). (May} be substituted with), C 3-7 cycloalkyl, C _1-6 alkyl sulfonyl, and C _1-6 alkyl carbonyl substituted with 1 to 4 groups of the same or different species selected from the group. May be)
, And (h) C _1-6 alkylsulfonyl (the group may be substituted with the same or different 1-3 halogen atoms).
It may be substituted with 1-3 groups of the same or different species selected from the group consisting of),
(3) C _3-12 cycloalkyl (the group is halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, C _1-6 alkyl It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of sulfonyl, mono- or di-C _{1-6 alkylaminocarbonyl),}
(4) C _3-7 cycloalkoxy (the group is 1 to 4 groups of the same type or different from each other selected from the group consisting of halogen atom, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with)
(5) C _6-10 aryl (the groups are halogen atoms, cyano, hydroxy, amino, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, and C _1- It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of _{6 alkylsulfonyls),}
(6) 4-membered to 10-membered saturated heterocyclic group (the group is selected from the group consisting of halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, and C _1-6 alkyl carbonyl. It may be substituted with 1 to 4 groups of the same or different species), or (7) 5-membered to 10-membered heteroaryl (the group is a halogen atom, cyano, C _1-6 alkyl, C _{1). It} may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of _-6 alcohols, mono- or di-C _1-6 alkylaminos, and C 1-6 alkylsulfonyls).
Can be mentioned.

Since the compound of the present invention may exist in the form of a hydrate and / or a solvate, a solvate such as these hydrates or an ethanol solvate is also included in the compound of the present invention. Furthermore, the compounds of the present invention also include those in crystalline form in all aspects.
Pharmaceutically acceptable salts of the compound represented by the formula (1) include, for example, hydrochlorides, hydrobromates, sulfates, phosphates, nitrates and other inorganic acid salts; and acetates. Propionate, oxalate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate , Organic acid salts such as ascorbate and the like can be mentioned as specific examples.

The compound (1) represented by the formula (1) may exist as a tautomer. Therefore, the compound of the present invention also includes tautomers of the compound represented by the formula (1).

The compound represented by the formula (1) may have at least one asymmetric carbon atom. Therefore, the compounds of the present invention include not only racemic compounds of the compounds represented by the formula (1) but also optically active compounds of these compounds.
Also included in either one or the compounds represented by more than one ¹ deuterium converter converted to ^H and ^{2 H} (D) be the formula (1) of the compound represented by formula (1) ..

Hereinafter, a method for producing a compound represented by the formula (1) in the present invention will be described with reference to an example, but the present invention is not limited thereto.

Production Method The compound of the present invention is synthesized by the following production method and a method combining a known compound and a known synthesis method.
The compounds in the reaction formula also include the case where they form salts, and examples of the salts include those similar to those of the salt of compound (1). It should be noted that these reactions are merely examples, and the compound of the present invention can be produced by other methods as appropriate based on the knowledge of a person who is proficient in organic synthesis.

In each of the production methods described below, even if the use of a protecting group is not specifically specified, if a functional group that requires protection exists, the functional group is protected as necessary. The desired product may be obtained by deprotecting after completion of the reaction or after performing a series of reactions.

As protecting groups, for example, the literature (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Willey and Sons, Inc., 19 (19), Inc., New. The usual protecting groups described in the above can be used, and more specifically, as the protecting group of the amino group, for example, tert-butoxycarbonyl, benzyloxycarbonyl, dimethylformamide, p-toluenesulfonyl, o- Nitrobenzenesulfonyl, tetrahydropyranyl and the like, as the protecting group of the hydroxy group, for example, trialkylsilyl, acetyl, benzyl, tetrahydropyranyl, methoxymethyl and the like, as the protecting group of the aldehyde group, for example, dialkylacetal, cyclic As the protecting group for the carboxyl group of alkyl acetal or the like, for example, tert-butyl ester, ortho ester, acid amide and the like can be mentioned.

The introduction and elimination of protecting groups is a method commonly used in synthetic organic chemistry (eg, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Son. , Inc., New York (1999), etc.) or a method similar thereto.

［式中、Ｒ^５、Ｗ^１は、前記〔１〕と同義であり；Ｘ^２ａは、単結合、−（ＣＨ_２）_ｋ−Ｃ（Ｏ）−を表し；ｋは、０、１または２を表し；Ｒ^１ｂは、置換されていてもよいＣ_１−６アルコキシ、置換されていてもよいＣ_３−７シクロアルコキシ、置換されていてもよい４員〜７員の飽和ヘテロ環基−オキシ、置換されていてもよいＣ_１−６アルキルチオ、または置換されていてもよいアミノを表し；Ｒ^２ｂは、置換されていてもよいＣ_１−６アルキル、または置換されていてもよいＣ_３−７シクロアルキルを表し；環Ｑ^２は、置換されていてもよいＣ_６−１０アリール、または置換されていてもよい５員〜１０員のヘテロアリールを表し；Ｈａｌ^ａおよびＨａｌ^ｂは、それぞれ独立して、塩素原子、臭素原子またはヨウ素原子を表し；Ｌは脱離基（例えば、ヨウ素原子、臭素原子、塩素原子、置換スルホニル基（例えば、メタンスルホニル基、ｐ-トルエンスルホニル基等）等）を表す。］ Manufacturing method 1
The compound represented by the formula (1-12) is produced, for example, by the method shown below.

[In the formula, R ⁵ and W ¹ are synonymous with [1] above; X ^2a represents a single bond, − (CH ₂ ) _k −C (O) −; k is 0, 1 or 2 Represents; R ^1b is _{optionally substituted C 1-6} alkoxy, optionally substituted C _3-7 cycloalkoxy, optionally substituted 4- to 7-membered saturated heterocyclic group-oxy. _{Represents C 1-6} alkylthio, which may be substituted, or amino, which may be ^{substituted; R 2b} _{is C 1-6} alkyl, which may be _{substituted, or C 3-,} which may be substituted. It represents _cycloalkyl; ring ^{Q 2} are optionally substituted _{C 6-10} aryl or substituted represents a heteroaryl may also be 5-membered to 10-membered,; Hal ^a and Hal ^b are each independently Represents a chlorine atom, a bromine atom or an iodine atom; L is a leaving group (for example, iodine atom, bromine atom, chlorine atom, substituted sulfonyl group (for example, methanesulfonyl group, p-toluenesulfonyl group, etc.)). Represents. ]

Step 1-1: Production of compound (1-2) Compound (1-2) can be obtained by reacting compound (1-1) with ammonia in the presence of a base in an inert solvent. .. As the compound (1-1), a commercially available product or a compound produced by a known synthetic method (for example, WO2014127816, Bioorganic and Medicinal Chemistry Letters, 4879, (2006), etc.) or a synthetic method based thereto can be used. ..

Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane; Aprotic polar solvents such as acetonitrile, propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; protic polarities such as water, methanol, ethanol, isopropanol Solvents; and mixed solvents thereof and the like. Tetrahydrofuran and methanol are preferable.

Specific examples of the base include, for example, triethylamine, diisopropylethylamine and the like.

The reaction temperature is not particularly limited, but is usually selected from the range from −78 ° C. to the boiling point of the solvent used. It is preferably −78 ° C. to 0 ° C. The reaction time is usually 30 minutes to 6 hours.

Step 1-2: Production step of compound (1-4) In compound (1-4), compound (1-2) is reacted with compound (1-3) in the presence of a base in an inert solvent. Can be obtained by As the compound (1-3), a commercially available product or a compound produced by a known synthetic method (for example, WO200874752, WO200616178, etc.) or a synthetic method similar thereto can be used.

Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; protons such as methanol, ethanol, 1-propanol, isopropanol and 1-butanol. Sexual polar solvents; and mixed solvents thereof and the like can be mentioned. Tetrahydrofuran is preferably a protic and aprotic solvent.

Specific examples of the base include metal alkoxides such as sodium methoxide, sodium ethoxide, sodium and sodium 1-propoxide; and metal hydrides such as sodium hydride.

The reaction temperature is not particularly limited, but is usually selected from the range from −20 ° C. to the boiling point of the solvent used. It is preferably −20 ° C. to 20 ° C. The reaction time is usually 30 minutes to 12 hours.

Step 1-3: Production Step of Compound (1-5) Compound (1-5) reacts compound (1-4) with di-tert-butyl dicarbonate in the presence of a base in an inert solvent. Can be obtained by

Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbon solvents such as toluene and xylene; chloroform, dichloromethane, etc. Halogenated hydrocarbons such as 1,2-dichloroethane; aprotic polar solvents such as acetonitrile, propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; Protic and aprotic solvents such as water, methanol, ethanol and isopropanol; and mixed solvents thereof and the like can be mentioned. Tetrahydrofuran, chloroform and dichloromethane are preferred.

Specific examples of the base include, for example, triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaminopyridine and the like. A combination of triethylamine or diisopropylethylamine and N, N-dimethylaminopyridine is preferred.

The diBoc compound produced as a by-product in this reaction can be converted to compound (1-5) by adding a metal alkoxide into the reaction system after confirming the disappearance of compound (1-4). As the metal alkoxide, sodium methoxide, sodium ethoxide, sodium, sodium 1-propoxide and the like are used.

The reaction temperature is not particularly limited, but is usually selected from the range from −20 ° C. to the boiling point of the solvent used. It is preferably 0 ° C to 20 ° C. The reaction time is usually 1 to 24 hours.

Step 1-4: Production step of compound (1-8) Compound (1-8) uses compound (1-5) in an inert solvent in the presence of Mitsunobu reagent and phosphine reagent, and compound (1-8). It can be obtained by reacting with 6). In addition, compound (1-8) is a compound (1) obtained by a method similar to a known synthetic method (for example, EP1550662, (2005), Journal of Medicinal Chemistry, 2964, (2010), etc.). It can also be obtained by reacting with -7). As the compound (1-6), a commercially available product or a compound produced by a known synthetic method (for example, WO200644454, WO201428669, etc.) or a synthetic method similar thereto can be used. As the compound (1-7), a commercially available product or a compound produced by a known synthetic method (for example, US2013 / 1503254, EP1679308, (2006), etc.) or a synthetic method similar thereto can be used.

Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene and xylene; chloroform, dichloromethane, 1, Halogenized hydrocarbons such as 2-dichloroethane; aprotic polar solvents such as acetonitrile, propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; and these. Examples thereof include a mixed solvent of. Tetrahydrofuran, toluene, dichloromethane and a mixed solvent thereof and the like are preferable.

Specific examples of the Mitsunobu reagent include diethyl azodicarboxylate, diisopropyl azodicarboxylate, dicyclohexyl azodicarboxylate, dibenzyl azodicarboxylate, tert-butyl azodicarboxylate, bis (2-methoxyethyl) azodicarboxylate, 1, Examples thereof include 1'-(azodicarbonyl) dipiperidin and 1,1'-azobis (N, N-dimethylformamide).

Specific examples of the phosphine reagent include triphenylphosphine, trimethylphosphine, tributylphosphine, trioctylphosphine and the like. Preferred are triphenylphosphine and tributylphosphine.

The reaction temperature is not particularly limited, but is usually selected from the range from −20 ° C. to the boiling point of the solvent used. It is preferably −20 ° C. to 60 ° C. The reaction time is usually 5 minutes to 72 hours.

Step 1-5: Production Step of Compound (1-9) Compound (1-9) can be obtained by reacting compound (1-8) with an acid in an inert solvent.

Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbon solvents such as toluene and xylene; methyl acetate and acetate. Ester solvents such as ethyl; halogenated hydrocarbon solvents such as chloroform, dichloromethane, 1,2-dichloroethane; acetonitrile, propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2 -Aprotonic polar solvents such as pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof and the like. Tetrahydrofuran, ethyl acetate, chloroform and dichloromethane are preferred.

Specific examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid; and organic acids such as trifluoroacetic acid.

The reaction temperature is not particularly limited, but is usually selected from the range from −20 ° C. to the boiling point of the solvent used. It is preferably 0 ° C to 30 ° C. The reaction time is usually 30 minutes to 24 hours.

Step 1-6: Production Step of Compound (1-10) Compound (1-10) can be obtained by reducing the nitro group of compound (1-9). For example, reduction under acidic conditions using a metal such as zinc, iron, tin or a metal salt such as tin (III) chloride; reduction using a sulfide such as sodium dithionate; palladium / carbon in a hydrogen atmosphere. , Raney nickel / carbon, platinum oxide / carbon, rhodium / carbon and other metal catalysts can be used for catalytic reduction.

In the reduction reaction using a metal or a metal salt, the amount of the metal or the metal salt used is usually 1 mol to 100 mol, preferably 2 mol to 20 mol, relative to 1 mol of the compound (1-9). The amount of the acid used is usually 1 mol to 100 mol, preferably 1 mol to 20 mol, relative to 1 mol of the compound (1-9). The reduction reaction is carried out in an inert solvent. For example, ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,2-dimethoxyethane; ester solvents such as methyl acetate and ethyl acetate; protonic polar solvents such as water, methanol, ethanol and isopropanol; And a mixed solvent thereof and the like. The reaction temperature is not particularly limited, but is usually selected from the range of 0 ° C. to 100 ° C. The reaction time is usually 30 minutes to 12 hours.

This reaction can be carried out in the presence of an acid, if necessary. As the acid, for example, an organic acid such as formic acid, acetic acid and trifluoroacetic acid, an inorganic acid such as ammonium chloride and the like are used. The amount of acid used is 0.1 mol or more per 1 mol of compound (2-9).

In the catalytic reduction reaction, the amount of the metal catalyst used is usually 0.1 to 1000% by weight, preferably 1 to 100% by weight, based on the compound (2-9). This reaction is carried out in an inert solvent. For example, ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,2-dimethoxyethane; ester solvents such as methyl acetate and ethyl acetate; protonic polar solvents such as water, methanol, ethanol and isopropanol; And a mixed solvent thereof and the like. The hydrogen pressure is usually about 1 to about 100 atm, preferably about 1 to about 5 atm. The reaction temperature is not particularly limited, but is usually 0 ° C. to 120 ° C., preferably 20 ° C. to 80 ° C. The reaction time is usually 30 minutes to 72 hours, preferably 1 hour to 24 hours.

This reaction can be carried out in the presence of an acid catalyst or a one-electron supplement, if necessary. As the acid catalyst, for example, organic acids such as formic acid, acetic acid and trifluoroacetic acid; and inorganic acids such as sulfuric acid, hydrochloric acid and hydrobromic acid are used. The amount of acid used is 0.1 mol or more per 1 mol of compound (1-9). As the one-electron supplement, for example, tetracyanoquinodimethane or the like is used. The amount of the one-electron supplement used is 0.005 mol or more per 1 mol of the compound (1-9).

Step 1-7: Production of Compound (1-12) Compound (1-12) reacts compound (1-10) with compound (1-11) in the presence of an oxidizing agent in an inert solvent. Can be obtained by As the compound (1-11), a commercially available product or a compound produced by a known synthetic method (for example, US200619965, Journal of Medicinal Chemistry, 3680, (2003), etc.) or a synthetic method similar thereto can be used.

Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,2-dimethoxyethane; acetonitrile, propionitrile, N, N-dimethylformamide, N, N. Examples thereof include aprotic polar solvents such as -dimethylacetamide, N-methyl-2-pyrrolidinone and dimethyl sulfoxide; protic polar solvents such as water, methanol, ethanol and isopropanol; and mixed solvents thereof. Preferred are N, N-dimethylformamide, dimethyl sulfoxide, water, ethanol and isopropanol.

Specific examples of the oxidizing agent include iron (III) chloride, oxone and the like.

The reaction temperature is not particularly limited, but is usually selected from the range from 0 ° C. to the boiling point of the solvent used. It is preferably 0 ° C to 100 ° C. The reaction time is usually 30 minutes to 24 hours.

［式中^１、Ｗ^１は、前記〔１〕と同義であり；Ｒ^１ｂ、Ｒ^２ｂおよびＱ^２は、製造法１と同義であり；Ｘ^２ｂは、−（ＣＨ_２）_ｋ−Ｃ（Ｏ）ＮＲ^ｅ−（ここにおいて、Ｒ^ｅは、水素原子または置換されていてもよいＣ_１−６アルキルを表し；ｋは、０、１または２を表す）を表し；Ｒ^５ａは、置換されていてもよいＣ_１−８アルキル、置換されていてもよいＣ_３−１２シクロアルキル、置換されていてもよいＣ_６−１０アリール、置換されていてもよい４員〜１０員の飽和ヘテロ環基、または置換されていてもよい５員〜１０員のヘテロアリールを表す。］ Manufacturing method 2
The compound represented by the formula (2-4) is produced, for example, by the method shown below.

[In the formula ¹ , W ¹ is synonymous with [1] above; R ^1b , R ^2b and Q ² are synonymous with manufacturing method 1; X ^2b is − (CH ₂ ) _k −C (O ) NR ^e − (where ^Re represents a hydrogen atom or optionally substituted C _1-6 alkyl; k represents 0, 1 or 2); R ^5a is substituted. C _1-8 alkyl _optionally substituted, C 3-12 cycloalkyl optionally substituted, C _6-10 aryl optionally substituted, 4-10 member saturated heterocyclic groups optionally substituted. Represents a 5- to 10-membered heteroaryl which may be substituted. ]

Step 2-1: Production of compound (2-3) Compound (2-3) uses compound (2-1) as a condensing agent, and if necessary, in the presence of a base and an additive in an inert solvent. , Produced by reacting with compound (2-2). As the compound (2-2), a commercially available product or a compound produced by a known synthetic method (for example, WO200870150, WO200870150, etc.) or a synthetic method similar thereto can be used. As the compound (2-1), a compound produced according to the method described in Production Method 1 can be used.

Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene and xylene; acetonitrile, propionitrile, etc. Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof and the like can be mentioned. Preferred are N, N-dimethylacetamide and N-methyl-2-pyrrolidinone.

Specific examples of the condensing agent include dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide, and benzotriazole-1-yl-tris (dimethylamino) phosphonium / hexafluorophosphate. Salt, diphenylphosphonyldiamide, N, N-carbonyldimidazole, O- (benzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate, O- (7) -Azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate and the like can be mentioned.

Specific examples of the additive include additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine. The reaction can be carried out.

Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus. Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride and the like; metal alkoxides such as sodium methoxydo and potassium tert-butoxide, etc. Be done.

The reaction temperature is not particularly limited, but is usually selected from a range of about −20 ° C. to the boiling point of the solvent used. It is preferably 0 ° C to 20 ° C. The reaction time is usually 10 minutes to 48 hours.

Compound (2-3) may be converted to compound (2-4) and produced under the production conditions of this step.

Step 2-2: Production step of compound (2-4) Compound (2-4) reacts with compound (2-3) with a silylating agent in an inert solvent in the presence of an additive as needed. Manufactured by allowing.

Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene and xylene; acetonitrile, propionitrile, etc. Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and theirs. Examples include a mixed solvent.

Specific examples of the additive include 1- (3-dimethylaminopropyl) 3-ethylurea, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydro-1, The reaction can be carried out by adding additives such as 2,3-benzotriazine, bis (trimethylsilyl) amine, pyridine, N, N-dimethyl-4-pyridine and pyridine.

Specific examples of the silylating agent include N, O-bis (trimethylsilyl) acetamide, N, O-bis (trimethylsilyl) trifluoroacetamide, trimethylchlorosilane and the like. Preferred are N, O-bis (trimethylsilyl) acetamide and N, O-bis (trimethylsilyl) trifluoroacetamide.

The reaction temperature is not particularly limited, but is usually selected from a range of about −20 ° C. to the boiling point of the solvent used. It is preferably 20 ° C to 150 ° C. The reaction time is usually 10 minutes to 48 hours.

［式中、Ｒ^３、環Ｑ^１、Ｗ^１、Ｗ^２、ｎは、前記〔１〕と同義であり；Ｒ^１ｂおよびＲ^２ｂは、製法１と同義であり；Ｒ^４ｂは、置換されていてもよいアミノ、置換されていてもよい４員〜１０員の飽和ヘテロ環基を表し；Ｒ^ｆは、置換スルホニル基（例えば、メタンスルホニル基、ｐ-トルエンスルホニル基等）等）を表す。］ Manufacturing method 3
The compound represented by the formula (3-4) is produced, for example, by the method shown below.

[In the formula, R ³ , ring Q ¹ , W ¹ , W ² , n are synonymous with [1] above; R ^1b and R ^2b are synonymous with formula 1; R ^4b is substituted. May represent an amino, optionally substituted 4- to 10-membered saturated heterocyclic group; R ^f represents a substituted sulfonyl group (eg, methanesulfonyl group, p-toluenesulfonyl group, etc.). ]

Step 3-1: Production of compound (3-2) Compound (3-2) can be obtained by reacting compound (3-1) with a base in an inert solvent. As the compound (3-1), a compound produced according to the method described in Production Method 1 can be used.

Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; protonic polar solvents such as methanol, ethanol and water; and mixtures thereof. Examples include a solvent. Tetrahydrofuran, methanol and ethanol are preferable.

Specific examples of the base include inorganic bases such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium trimethylsilyl oxide and sodium trimethylsilyl oxide. , Organic bases such as potassium trimethylsilyl oxide and the like. Lithium hydroxide, sodium hydroxide and potassium hydroxide are preferable.

The reaction temperature is not particularly limited, but is usually selected from the range from −20 ° C. to the boiling point of the solvent used. It is preferably −20 ° C. to 60 ° C. The reaction time is usually 30 minutes to 48 hours.

Step 3-2: Production step of compound (3-4) Compound (3-4) is a compound obtained by mixing compound (3-2) in an inert solvent in the presence of Mitsunobu reagent and phosphine reagent, or Kakuda reagent. It can be obtained by reacting with (3-3). As the compound (3-3), a commercially available product or a compound produced by a known synthetic method (for example, US2003220341, US2003229092, etc.) or a synthetic method similar thereto can be used. As the compound (3-2), a compound produced according to the method described in Production Method 1 can be used.

Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene and xylene; chloroform, dichloromethane, 1, Halogenized hydrocarbons such as 2-dichloroethane; aprotic polar solvents such as acetonitrile, propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; and these. Examples thereof include a mixed solvent of. Tetrahydrofuran, toluene and a mixed solvent thereof and the like are preferable.

Specific examples of the Mitsunobu reagent include diethyl azodicarboxylate, diisopropyl azodicarboxylate, dicyclohexyl azodicarboxylate, dibenzyl azodicarboxylate, tert-butyl azodicarboxylate, bis (2-methoxyethyl) azodicarboxylate, 1, Examples thereof include 1'-(azodicarbonyl) dipiperidin and 1,1'-azobis (N, N-dimethylformamide). Preferred are diethyl azodicarboxylate and diisopropyl azodicarboxylate.

Specific examples of the phosphine reagent include triphenylphosphine, trimethylphosphine, tributylphosphine, trioctylphosphine and the like. Preferred are triphenylphosphine and tributylphosphine.

Specific examples of the Kakuda reagent include (cyanomethylene) tributylphosphorane and (cyanomethylene) trimethylphosphorane. Preferred is (cyanomethylene) tributylphosphorane.

The reaction temperature is not particularly limited, but is usually selected from the range from −20 ° C. to the boiling point of the solvent used. It is preferably 0 ° C to 100 ° C. The reaction time is usually 10 minutes to 72 hours.

［式中、Ｒ^３、環Ｑ^１、Ｗ^１、ｎは、前記〔１〕と同義であり；Ｒ^１ｂおよびＲ^２ｂは、製法１と同義であり；Ｈａｌ^ｃは、塩素原子、臭素原子またはヨウ素原子を表し；Ａは、ボロン酸、ボロン酸エステル、ＢＦ_３Ｋ、またはＢＦ_３Ｎａを表し；Ｑ^３は、置換されていてもよい４員〜１０員の部分不飽和のヘテロ環基を表し；Ｑ^４は、置換されていてもよい４員〜１０員の飽和ヘテロ環基を表す。］ Manufacturing method 4
The compound represented by the formula (4-4) is produced, for example, by the method shown below.

Wherein, ^{R 3,} ring ^{Q 1, W} 1, n is the (1) in the above ^{formula; R 1b} and ^{R 2b} are as defined for formula 1; Hal ^c is a chlorine atom, a bromine atom or Represents an iodine atom; A represents boronic acid, boronic acid ester, BF ₃ K, or BF ₃ Na; Q ³ represents a optionally substituted 4- to 10-membered partially unsaturated heterocyclic group. It represents; Q ⁴ represents a saturated heterocyclic group of 10-membered optionally substituted 4- to membered. ]

Step 4-1: Production of compound (4-3) Compound (4-3) contains compound (4-1) in an inert solvent with a base and palladium catalyst, and if necessary, the presence of a phosphine ligand. It can be obtained by reacting with compound (4-2) below. Compound (4-2) is a product produced as a commercially available product or by a known synthetic method (for example, Journal of Organic Chemistry 7508 (1995), Angewandte Chemie International Edition 928 (2008), etc.) or a synthetic method similar thereto. Can be used. As the compound (4-1), a compound produced according to the method described in Production Method 1 can be used.

Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene and xylene; acetonitrile, propionitrile, etc. Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; protic polar solvents such as water; and mixed solvents thereof and the like can be mentioned.

Specific examples of the palladium catalyst include zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, and tris (dibenzylideneacetone) dipalladium; bis (triphenylphosphine) palladium dichloride, acetic acid. Examples thereof include divalent catalysts such as palladium and bis (diphenylphosphinoferosen) palladium dichloride. It is preferably tetrakistriphenylphosphine palladium or palladium acetate.

Specific examples of the phosphine ligand include o-tolylphosphine, 2-dicyclohexylphosphino-2', 6'-dimethoxy-1,1'-biphenyl, 2-dicyclohexylphosphino-2', 4', and so on. Monodentate ligands such as 6'-triisopropyl-1,1'-biphenyl; 1,1'-bis (diphenylphosphino) ferrocene, 1,2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, 9,9-dimethyl-4,5 Examples thereof include bidentate ligands such as −bis (diphenylphosphino) xanthin and bis (2-diphenylphosphinophenyl) ether.

Specific examples of the base include, for example, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, and phosphoric acid. Examples thereof include inorganic bases such as disodium hydrogen hydrogen, sodium phosphate, potassium hydroxide and sodium hydroxide. It is preferably sodium carbonate, potassium carbonate or potassium phosphate.

The reaction temperature is not particularly limited, but is selected from a temperature between room temperature and the boiling point of the solvent used, preferably 60 ° C. to 140 ° C., or 80 ° C. to 140 ° C. under microwave irradiation. The reaction time is usually 30 minutes to 24 hours.

Step 4-2: Production step of compound (4-4) Compound (4-4) is obtained by subjecting compound (4-3) to catalytic reduction using a metal catalyst in an inert solvent under a hydrogen atmosphere. Obtainable.

Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; ester solvents such as methyl acetate and ethyl acetate; water, methanol and ethanol. , Proponic polar solvents such as isopropanol; and mixed solvents thereof and the like.

Specific examples of the metal catalyst include palladium / carbon, palladium / carbon hydroxide, Raney nickel, platinum oxide / carbon, rhodium / carbon and the like. Palladium / carbon and palladium / carbon hydroxide are preferable. The amount of the metal catalyst used is usually 0.1 to 1000% by weight, preferably 1 to 100% by weight, based on the compound (4-3).

This reaction can be carried out in the presence of an acid, if necessary. As the acid, formic acid, acetic acid, organic acids such as trifluoroacetic acid and the like are used, for example. The amount of acid used is 0.1 mol or more per 1 mol of compound (7-3).

The hydrogen pressure is usually about 1 to about 100 atm, preferably about 1 to about 5 atm. The reaction temperature is not particularly limited, but is usually 0 ° C. to 120 ° C., preferably 20 ° C. to 80 ° C. The reaction time is usually 30 minutes to 72 hours, preferably 1 hour to 24 hours.

［式中、Ｒ^３、環Ｑ^１、Ｗ^１、ｎは、前記〔１〕と同義であり；Ｒ^１ｂおよびＲ^２ｂは、製法１と同義であり；Ｒ^１ｃおよびＲ^１ｄは、それぞれ独立して、水素原子または置換されていてもよいＣ_１−６アルキルを表すか；Ｒ^ｃおよびＲ^ｄは、それらが結合する窒素原子と一緒になって、置換されていてもよい４員〜１０員の飽和ヘテロ環を形成していてもよい。］ Manufacturing method 5
The compound represented by the formula (5-5) is produced, for example, by the method shown below.

[In the formula, R ³ , ring Q ¹ , W ¹ , n are synonymous with [1] above; R ^1b and R ^2b are synonymous with manufacturing method 1; R ^1c and R ^1d are independent of each other. Represents a hydrogen atom or a C _1-6 alkyl which ^{may be substituted; R c} and R ^d are 4 to 10 members which may be substituted together with the nitrogen atom to which they are attached. May form a saturated heterocycle of. ]

Step 5-1: Production of Compound (5-3) Compound (5-3) comprises compound (5-1) in an inert solvent in the presence of a boron hydride compound and, if necessary, an acid. It can also be obtained by reacting with compound (5-2). As the compound (5-2), a commercially available product or a compound produced by a known synthetic method (for example, WO20073965, US2010216812, etc.) or a synthetic method similar thereto can be used. As the compound (5-1), a compound produced according to the method described in Production Method 1 can be used.

Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane; Protonic polar solvents such as methanol, ethanol, 1-propanol, 2-propanol, and water; and mixed solvents thereof and the like can be mentioned. Tetrahydrofuran, dichloromethane, chloroform and methanol are preferable.

Specific examples of the acid include carboxylic acids such as formic acid, propionic acid, acetic acid and trifluoroacetic acid; and mineral acids such as hydrochloric acid.

Specific examples of the boron borohydride compound include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride and the like. Sodium cyanoborohydride and sodium triacetoxyborohydride are preferred.

The reaction temperature is not particularly limited, but is usually selected from the range from 0 ° C. to the boiling point of the solvent used. It is preferably 0 ° C to 20 ° C. The reaction time is usually 30 minutes to 72 hours.

Step 5-2: Production Step of Compound (5-4) Compound (5-4) is produced by producing compound (5-3) according to the method described in Step 1-5.

Step 5-3: Production step of compound (5-5) Compound (5-5) is produced from compound (5-4) according to the method described in step 1-6.

By carrying out the above production methods in an appropriate combination, the compound of the present invention having a desired functional group at a desired position can be obtained. Isolation and purification of intermediates and products in the above production method shall be carried out by appropriately combining methods used in ordinary organic synthesis, such as filtration, extraction, washing, drying, concentration, crystallization, and various types of chromatography. Can be done. Further, the intermediate can be subjected to the next reaction without any particular purification.
Depending on the reaction conditions and the like, the raw material compound or intermediate in the above production method may exist in the form of a salt such as hydrochloride, but can be used as it is or in a free form. When the raw material compound or intermediate is obtained in the form of a salt and the raw material compound or intermediate is to be used or obtained in free form, they are dissolved or suspended in a suitable solvent, for example, a base such as an aqueous sodium hydrogen carbonate solution. It can be converted to a free form by neutralizing with or the like.

Compounds (1) or pharmaceutically acceptable salts thereof may contain isomers such as keto-enol, positional isomers, geometric isomers or optical isomers. All possible isomers, including these, and mixtures of the isomers in any proportion are also included in the invention.
Further, the optical isomer can be separated by carrying out a known separation step such as a method using an optically active column or a fractional crystallization method in an appropriate step of the above-mentioned production method. An optically active substance can also be used as a starting material.

When it is desired to obtain a salt of compound (1), if a salt of compound (1) can be obtained, it can be purified as it is, and if compound (1) can be obtained in a free form, compound (1) is suitable. It may be dissolved or suspended in a solvent and an acid or base may be added to form a salt. In addition, compound (1) or a pharmaceutically acceptable salt thereof may exist in the form of a solvate with water or various solvents, and these solvates are also included in the present invention.

An autoimmune disease is an abnormality in the natural immune system that should play a role in recognizing and eliminating foreign substances such as pathogenic microorganisms that originally invaded from the outside. It is a general term for diseases in which antibodies and lymphocytes are excessively produced, causing inflammation accompanied by systemic or organ-specific cytokine production, leading to tissue damage. Specifically, systemic lupus erythematosus, lupus nephritis, central nervous system lupus, cutaneous lupus erythematosus (eg, discoid lupus erythematosus, deep lupus erythematosus), Schegren's syndrome, idiopathic thrombocytopenic purpura, autoimmune blood disorders (eg, discoid lupus erythematosus, deep lupus erythematosus) For example, autoimmune hemolytic anemia, idiopathic thrombocytopenia, etc.), psoriasis (eg psoriasis vulgaris, arthritic psoriasis, pustular psoriasis, lupus erythematosus), lupus erythematosus (eg lupus erythematosus, vesicles Lupus erythematosus), rheumatoid arthritis, antiphospholipid antibody syndrome, Ecardi-Gutierre syndrome, IgG4-related diseases, polymyositis, dermatomyositis, Bechet's disease, type I diabetes, acute progressive glomerulonephritis, polysclerosis, Crohn's disease, ulcerative colitis, Hashimoto's disease, psoriasis, systemic dermatomyositis, nodular polyarteritis, allergic granulomatous vasculitis, primary mucinous edema, thyroid poisoning, malignant anemia, Good Pasture syndrome , Severe myasthenia, insulin-resistant diabetes, juvenile diabetes, psoriasis, atrophic gastric inflammation, male infertility, premature menopause, lupus erythematosus, primary biliary cirrhosis, chronic active hepatitis, seizures Examples include lupus erythematosus, primary lupus erythematosus, Giran Valley syndrome, Basedou's disease, interstitial lupus erythematosus and mixed connective tissue disease.

The pharmaceutical preparation according to the present invention is produced by mixing the active ingredient with one or more pharmaceutically acceptable carriers and using any method well known in the technical field of pharmaceutics. Examples of the pharmaceutical carrier used include lactose, mannitol, glucose, starch, magnesium stearate, glycerate, distilled water for injection, physiological saline, propylene glycol, polyethylene glycol, ethanol and the like. In addition, the pharmaceutical preparation according to the present invention may contain various other excipients, lubricants, lubricants, binders, disintegrants, isotonic agents, emulsifiers and the like.

As the administration route, it is desirable to use the most effective route for treatment, and oral administration or parenteral administration such as intravenous, application, inhalation and eye drops can be mentioned, but oral administration is preferable. Examples of the administration form include tablets, injections and the like, but tablets are preferable. The dose and frequency of administration of these pharmaceutical compositions vary depending on the administration form, the patient's disease and symptoms, the age and weight of the patient, etc., and cannot be unconditionally specified, but are usually effective for adults per day. The amount of the component is in the range of about 0.0001 to about 5000 mg, preferably in the range of about 0.001 to about 1000 mg, more preferably in the range of about 0.1 to about 500 mg, and particularly preferably in the range of about 1 to about 300 mg. It can be administered several times a day, preferably divided into 1 to 3 times a day.

The compound of the present invention can be used in combination with other drugs for the purpose of enhancing its effect and / or reducing side effects. Specifically, the compound of the present invention can be used in combination with a drug such as a steroid drug, an immunosuppressive drug, a drug that targets B cells, or a drug that inhibits TLR. Here, the “drug targeting B cells” means an antibody drug targeting B cells. Examples of the "drug that inhibits TLR" include hydroxychloroquine, chloroquine and the like.
Hereinafter, a drug that can be used in combination with the compound of the present invention is abbreviated as a concomitant drug.

Concomitant medications include, for example, steroids, immunosuppressants, B cell targeting agents, TLR inhibitors, and other therapeutic agents for autoimmune diseases.

The administration period of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or at different times. Further, it may be a mixture of the compound of the present invention and a concomitant drug. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration target, administration route, target disease, symptom, combination and the like. For example, when the administration target is a human, 0.01 to 100 parts by weight of the concomitant drug may be used with respect to 1 part by weight of the compound of the present invention. In addition, for the purpose of suppressing the side effects, it can be used in combination with drugs (combined drugs) such as antiemetics, sleep-inducing agents, and anticonvulsants.

The dose varies depending on the individual compound and the patient's disease, age, body weight, sex, symptoms, route of administration, etc., but usually, for an adult (body weight 50 kg), 0.1 to 1000 mg of the compound of the present invention is used. / Day, preferably 0.1 to 300 mg / day, is administered once daily or in 2 to 3 divided doses. It can also be administered once every few days to several weeks.

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited to this. The compound names shown in the following examples and reference examples do not necessarily follow the IUPAC nomenclature.

The following abbreviations may be used herein.
(Boc) ₂ O: Di-tert-butyl dicarbonate Tf: TrifluoromethanesulfonylDMAP: N, N-dimethyl-4-aminopyridine EDCI: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide EDCI · HCl: 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride HOBt: 1-hydroxybenzotriazole HOBt · H ₂ O: 1-hydroxybenzotriazole monohydrate Boc: tert-butoxycarbonyl Me: methyl Et: ethyl Tf: TrifluoromethanesulfonylRt: Retention time

In the examples and reference examples, the following reactors were used as needed.
Microwave reactor: Biotage AB Initiator

The physicochemical data of each compound of Examples and Reference Examples was acquired by the following equipment.
^{1 1} H-NMR: JEOL JNM-AL400; Bruker AVANCE 400 Spectrometer

LC / MS data of each compound of Examples and Reference Examples was acquired by the following equipment.
Detection device: ACQUITY (registered trademark) SQ detacher (Waters)
HPLC: ACQUITY UPLC®
SYSTEM Volume: Waters ACQUITY UPLC® BEH C18 (1.7 μm, 2.1 mm x 30 mm)
The analysis conditions are as follows.

流速：０．８ｍＬ／ｍｉｎ；検出ＵＶ：２２０ｎｍ ａｎｄ ２５４ｎｍ；温度：４０℃

Flow velocity: 0.8 mL / min; Detection UV: 220 nm and 254 nm; Temperature: 40 ° C.

Compound names in Examples and Reference Examples were named by ACD / Name (ACD / Labs12.0, Advanced Chemistry Development Inc.).

参考例２６の化合物（７０．６ｍｇ）の２−プロパノール溶液（４ｍＬ）に室温下、３−メチルブタナール（０．０３０ｍｌ）と塩化鉄（ＩＩＩ）（９０．０ｍｇ）を加え反応混合物を加熱還流した。反応混合物を５．５時間撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルム/メタノールで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（７２．９ｍｇ）を得た。
LC-MS [M+H]^＋/Rt (min)： 454.3/0.747 (Method A); ¹H-NMR (400 MHz, CDCl₃) δ: 6.98 (1H, dd, J = 8.5, 9.8 Hz), 6.58-6.49 (2H, m), 5.29 (2H, s), 4.30-4.23 (1H, m), 4.01 (3H, s), 3.24-3.18 (1H, m), 2.96-2.87 (1H, m), 2.87-2.68 (4H, m), 2.72 (3H, s), 2.66 (2H, d, J = 6.7 Hz), 2.22-2.12 (1H, m), 2.12-2.04 (1H, m), 1.94-1.82 (1H, m), 1.76-1.61 (1H, m), 1.56-1.44 (1H, m), 1.40-1.27 (1H, m), 0.94 (6H, d, J = 6.7 Hz). Example 1
9-[(4-{[(3S) -1-azabicyclo [2.2.2] octane-3-yl] oxy} -2-fluorophenyl) methyl] -2-methoxy-6-methyl-8-( 2-Methylpropyl) -9H-purine

At room temperature, 3-methylbutanal (0.030 ml) and iron (III) chloride (90.0 mg) were added to a 2-propanol solution (4 mL) of the compound (70.6 mg) of Reference Example 26, and the reaction mixture was heated under reflux. did. The reaction mixture was stirred for 5.5 hours, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform / methanol. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (chloroform / methanol) to give the title compound (72.9 mg).
LC-MS [M + H] ⁺ / Rt (min): 454.3 / 0.747 (Method A); ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.98 (1H, dd, J = 8.5, 9.8 Hz), 6.58-6.49 (2H, m), 5.29 (2H, s), 4.30-4.23 (1H, m), 4.01 (3H, s), 3.24-3.18 (1H, m), 2.96-2.87 (1H, m), 2.87-2.68 (4H, m), 2.72 (3H, s), 2.66 (2H, d, J = 6.7 Hz), 2.22-2.12 (1H, m), 2.12-2.04 (1H, m), 1.94-1.82 ( 1H, m), 1.76-1.61 (1H, m), 1.56-1.44 (1H, m), 1.40-1.27 (1H, m), 0.94 (6H, d, J = 6.7 Hz).

参考例３１の化合物（４６．９ｍｇ）に室温下、Ｎ，Ｏ−ビス（トリメチルシリル）アセトアミド（０．０３０ｍｌ）を加え反応混合物を８５℃に加熱した。反応混合物を５時間撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルム/メタノールで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（１６．２ｍｇ）を得た。
LC-MS [M+H]^＋/Rt (min)： 551.2/0.848 (Method A); ¹H-NMR (400 MHz, DMSO-D₆) δ: 11.28 (1H, brs), 7.34-7.21 (2H, m), 7.21-7.13 (2H, m), 6.80-6.53 (3H, m), 5.44 (2H, s), 4.45-4.39 (1H, m), 3.79 (3H, s), 3.24-3.16 (1H, m), 2.77-2.60 (4H, m), 2.60-2.43 (1H, m), 2.43 (3H, s), 2.03-1.97 (1H, m), 1.80-1.66 (1H, m), 1.66-1.47 (2H, m), 1.33-1.22 (1H, m). Example 2
9-[(4-{[(3S) -1-azabicyclo [2.2.2] octane-3-yl] oxy} -2-fluorophenyl) methyl] -N- (4-chlorophenyl) -2-methoxy -6-Methyl-9H-Purin-8-carboxyamide

N, O-bis (trimethylsilyl) acetoamide (0.030 ml) was added to the compound (46.9 mg) of Reference Example 31 at room temperature, and the reaction mixture was heated to 85 ° C. The reaction mixture was stirred for 5 hours, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform / methanol. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (chloroform / methanol) to give the title compound (16.2 mg).
LC-MS [M + H] ⁺ / Rt (min): 551.2 / 0.848 (Method A); ¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 11.28 (1H, brs), 7.34-7.21 (2H) , m), 7.21-7.13 (2H, m), 6.80-6.53 (3H, m), 5.44 (2H, s), 4.45-4.39 (1H, m), 3.79 (3H, s), 3.24-3.16 (1H) , m), 2.77-2.60 (4H, m), 2.60-2.43 (1H, m), 2.43 (3H, s), 2.03-1.97 (1H, m), 1.80-1.66 (1H, m), 1.66-1.47 (2H, m), 1.33-1.22 (1H, m).

Examples 3-26
Compounds of Examples 3 to 26 were obtained using the corresponding raw material compounds according to the methods described in Examples 1 and 2.

実施例１３の化合物（３３．１ｍｇ）のピリジン溶液（１ｍＬ）に室温下、無水酢酸（０．０１５ｍｌ）を加えた。室温で反応混合物を５時間撹拌した後、トルエンを加え、減圧濃縮した。残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（３２．８ｍｇ）を得た。
LC-MS [M+H]^＋/Rt (min)： 495.2/0.567 (Method A); ¹H-NMR (400 MHz, CDCl₃) δ: 7.07-7.00 (1H, m), 6.60-6.51 (2H, m), 5.22 (2H, s), 4.71-4.64 (1H, m), 4.38-4.31 (1H, m), 4.31-4.25 (1H, m), 4.23-4.15 (1H, m), 4.12-4.04 (1H, m), 4.04 (3H, s), 4.00-3.90 (1H, m), 3.27-3.18 (1H, m), 2.97-2.87 (1H, m), 2.87-2.70 (4H, m), 2.74 (3H, s), 2.12-2.06 (1H, m), 1.95-1.83 (1H, m), 1.88 (3H, s), 1.77-1.68 (1H, m), 1.52-1.48 (1H, m), 1.41-1.30 (1H, m). Example 27
1-(3- {9-[(4-{[(3S) -1-azabicyclo [2.2.2] octane-3-yl] oxy} -2-fluorophenyl) methyl] -2-methoxy-6 −Methyl-9H-purine-8-yl} azetidine-1-yl) ethane-1-one

Acetic anhydride (0.015 ml) was added to a pyridine solution (1 mL) of the compound of Example 13 (33.1 mg) at room temperature. The reaction mixture was stirred at room temperature for 5 hours, toluene was added, and the mixture was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (chloroform / methanol) to give the title compound (32.8 mg).
LC-MS [M + H] ⁺ / Rt (min): 495.2 / 0.567 (Method A); ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.07-7.00 (1H, m), 6.60-6.51 (2H) , m), 5.22 (2H, s), 4.71-4.64 (1H, m), 4.38-4.31 (1H, m), 4.31-4.25 (1H, m), 4.23-4.15 (1H, m), 4.12-4.04 (1H, m), 4.04 (3H, s), 4.00-3.90 (1H, m), 3.27-3.18 (1H, m), 2.97-2.87 (1H, m), 2.87-2.70 (4H, m), 2.74 (3H, s), 2.12-2.06 (1H, m), 1.95-1.83 (1H, m), 1.88 (3H, s), 1.77-1.68 (1H, m), 1.52-1.48 (1H, m), 1.41 -1.30 (1H, m).

参考例２６の化合物（１１６ｍｇ）のクロロホルム溶液（２ｍＬ）にＥＤＣＩ・ＨＣｌ（１７３ｍｇ）、ＨＯＢｔ（１２２ｍｇ）、ベンゾイルぎ酸（１５２ｍｇ）、ジイソプロピルエチルアミン（０．３１ｍＬ）を加え、室温で２時間撹拌した後、終夜静置した。反応混合物を直接シリカゲルカラムクロマトグラフィー（クロロホルム／メタノールと酢酸エチル／メタノール）にて２回精製し、目的物を含むフラクションを濃縮した。残渣に酢酸エチルを加え、１ｍｏｌ／Ｌ塩酸水溶液で抽出した。水相からクロロホルムで目的物を抽出し、硫酸ナトリウムで乾燥、ろ過後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（２６ｍｇ）を得た。
LC-MS [M+H]^＋/Rt (min)： 502.3/0.811 (Method B); ¹H-NMR (CDCl₃) δ: 8.35-8.28 (2H, m), 7.50-7.44 (3H, m), 7.20 (1H, t, J = 8.8 Hz), 6.56-6.48 (2H, m), 5.62 (2H, s), 4.30-4.22 (1H, m), 4.06 (3H, s), 3.24-3.16 (1H, m), 2.94-2.68 (8H, m), 2.08-2.05 (1H, m), 1.93-1.85 (1H, m), 1.76-1.59 (1H, m), 1.54-1.44 (1H, m), 1.38-1.28 (1H, m). Example 28
{9-[(4-{[(3S) -1-azabicyclo [2.2.2] octane-3-yl] oxy} -2-fluorophenyl) methyl] -2-methoxy-6-methyl-9H- Purin-8-yl} (phenyl) methanone

EdCI-HCl (173 mg), HOBt (122 mg), benzoyl silicate (152 mg), and diisopropylethylamine (0.31 mL) were added to a chloroform solution (2 mL) of the compound (116 mg) of Reference Example 26, and the mixture was stirred at room temperature for 2 hours. After that, it was left to stand all night. The reaction mixture was directly purified twice by silica gel column chromatography (chloroform / methanol and ethyl acetate / methanol), and the fraction containing the desired product was concentrated. Ethyl acetate was added to the residue, and the mixture was extracted with a 1 mol / L hydrochloric acid aqueous solution. The desired product was extracted from the aqueous phase with chloroform, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (26 mg).
LC-MS [M + H] ⁺ / Rt (min): 502.3 / 0.811 (Method B); ¹ H-NMR (CDCl ₃ ) δ: 8.35-8.28 (2H, m), 7.50-7.44 (3H, m) , 7.20 (1H, t, J = 8.8 Hz), 6.56-6.48 (2H, m), 5.62 (2H, s), 4.30-4.22 (1H, m), 4.06 (3H, s), 3.24-3.16 (1H) , m), 2.94-2.68 (8H, m), 2.08-2.05 (1H, m), 1.93-1.85 (1H, m), 1.76-1.59 (1H, m), 1.54-1.44 (1H, m), 1.38 -1.28 (1H, m).

実施例２６の化合物（６６ｍｇ）のメタノール溶液（５ｍＬ）に３６％ホルムアルデヒド水溶液（０．０２２ｍＬ）を加え、室温で１５分攪拌した後、水素化ホウ素ナトリウム（２４ｍｇ）を加え、室温で２時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液と飽和食塩水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、ろ過後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（６０ｍｇ）を得た。
LC-MS ([M+H]^＋/Rt (min))： 468.2/0.652 (Method B); ¹H-NMR (CDCl₃) δ: 7.00 (1H, t, J = 8.8 Hz), 6.56-6.45 (2H, m), 5.29 (2H, s), 4.47-4.42 (1H, m), 4.01 (3H, s), 3.22-3.14 (2H, m), 2.72 (3H, s), 2.66 (2H, d, J = 7.3 Hz), 2.37-1.22 (12H, m), 0.95 (6H, d, J = 6.7 Hz). Example 29
9-[(2-Fluoro-4-{[(1R, 3r, 5S) -8-methyl-8-azabicyclo [3.2.1] octane-3-yl] oxy} phenyl) methyl] -2-methoxy -6-Methyl-8- (2-methylpropyl) -9H-purine

A 36% formaldehyde aqueous solution (0.022 mL) was added to a methanol solution (5 mL) of the compound (66 mg) of Example 26, and the mixture was stirred at room temperature for 15 minutes, sodium borohydride (24 mg) was added, and the mixture was stirred at room temperature for 2 hours. did. A saturated aqueous sodium hydrogen carbonate solution and a saturated brine were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (60 mg).
LC-MS ([M + H] ⁺ / Rt (min)): 468.2 / 0.652 (Method B); ¹ H-NMR (CDCl ₃ ) δ: 7.00 (1H, t, J = 8.8 Hz), 6.56-6.45 (2H, m), 5.29 (2H, s), 4.47-4.42 (1H, m), 4.01 (3H, s), 3.22-3.14 (2H, m), 2.72 (3H, s), 2.66 (2H, d) , J = 7.3 Hz), 2.37-1.22 (12H, m), 0.95 (6H, d, J = 6.7 Hz).

キヌクリジン―３−オン（５．３４ｇ）のテトラヒドロフラン（２２０ｍＬ）溶液に−７８℃でリチウムビス（トリメチルシリル）アミド（１．３ｍｏｌ／ｌ、５８．４ｍｌ）を加えた。３０分間撹拌した後、Ｎ−フェニルトリフルオロメタンスルホンアミド（１４．１５ｇ）を加え、−７８℃にて１時間撹拌した後、室温まで昇温し２時間攪拌した。反応混合物を０℃に冷却後、水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（６．１５ｇ）を得た。
LC-MS [M+H]^＋/Rt (min)： 258.1/0.374 (Method B); ¹H-NMR (400 MHz, CDCl₃) δ: 6.47 (1H, d, J = 2.3 Hz), 3.01-2.91 (2H, m), 2.87-2.82 (1H, m), 2.69-2.59 (2H, m), 1.90-1.73 (4H, m). Reference example 1
1-Azabicyclo [2.2.2] Oct-2-en-3-yl Trifluoromethanesulfonate

Lithium bis (trimethylsilyl) amide (1.3 mol / l, 58.4 ml) was added to a solution of quinuclidine-3-one (5.34 g) in tetrahydrofuran (220 mL) at −78 ° C. After stirring for 30 minutes, N-phenyltrifluoromethanesulfonamide (14.15 g) was added, and the mixture was stirred at −78 ° C. for 1 hour, then heated to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0 ° C., water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (6.15 g).
LC-MS [M + H] ⁺ / Rt (min): 258.1 / 0.374 (Method B); ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.47 (1H, d, J = 2.3 Hz), 3.01- 2.91 (2H, m), 2.87-2.82 (1H, m), 2.69-2.59 (2H, m), 1.90-1.73 (4H, m).

参考例１の化合物（１ｇ）の１，４−ジオキサン（２０ｍＬ）溶液に、ビスピナコラートジボラン（９８７ｍｇ）、酢酸カリウム（７６３ｍｇ）、１，１’−ビス（ジフェニルホスフィノ）フェロセンパラジウムクロリド（２３１ｍｇ）、１，１’−ビス（ジフェニルホスフィノ）フェロセン（７８ｍｇ）を加え、９０℃にて２時間攪拌した。反応混合物に４−ブロモ−２−フルオロ安息香酸メチル（８２４ｍｇ）、炭酸カリウム（９７７ｍｇ）、１，１’−ビス（ジフェニルホスフィノ）フェロセンパラジウムクロリド（２３１ｍｇ）、水（３ｍｌ）を加え、８０℃にて２時間攪拌した。反応混合物を室温に冷却後、水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（８４０ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.94-7.88 (1H, m), 7.26-7.22 (1H, m), 7.16 (1H, dd, J = 12.2, 1.8 Hz), 6.95 (1H, d, J = 1.8 Hz), 3.93 (3H, s), 3.15-3.11 (1H, m), 3.06-2.98 (2H, m), 2.68-2.58 (2H, m), 1.83-1.74 (2H, m), 1.60-1.50 (2H, m). Reference example 2
Methyl 4- (1-azabicyclo [2.2.2] octo-2-en-2-yl) -2-fluorobenzoate

Bispinacolat diborane (987 mg), potassium acetate (763 mg), 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (231 mg) in a solution of compound (1 g) of Reference Example 1 in 1,4-dioxane (20 mL). ), 1,1'-bis (diphenylphosphino) ferrocene (78 mg) was added, and the mixture was stirred at 90 ° C. for 2 hours. Methyl 4-bromo-2-fluorobenzoate (824 mg), potassium carbonate (977 mg), 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (231 mg), and water (3 ml) were added to the reaction mixture at 80 ° C. Was stirred for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (chloroform / methanol) to give the title compound (840 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.94-7.88 (1H, m), 7.26-7.22 (1H, m), 7.16 (1H, dd, J = 12.2, 1.8 Hz), 6.95 (1H, d) , J = 1.8 Hz), 3.93 (3H, s), 3.15-3.11 (1H, m), 3.06-2.98 (2H, m), 2.68-2.58 (2H, m), 1.83-1.74 (2H, m), 1.60-1.50 (2H, m).

参考例２の化合物（２７３ｍｇ）のエタノール溶液（２ｍＬ）に２０％水酸化パラジウム炭素（１１０ｍｇ）を加えた。水素雰囲気下、室温で３時間撹拌し、反応混合物をろ過した後、減圧濃縮した。残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（２２３ｍｇ）を得た。
LC-MS [M+H]^＋/Rt (min)： 263.9/0.368 (Method B); ¹H-NMR (400 MHz, CDCl₃) δ: 7.90 (1H, dd, J = 7.9, 12.8 Hz), 7.10 (1H, d, J = 7.9 Hz), 7.05 (1H, d, J = 12.8 Hz), 3.92 (3H, s), 3.39-3.27 (1H, m), 3.08-2.79 (6H, m), 1.99-1.93 (1H, m), 1.78-1.69 (2H, m), 1.66-1.55 (1H, m), 1.44-1.33 (1H, m). Reference example 3
Methyl 4- (1-azabicyclo [2.2.2] octane-2-yl) -2-fluorobenzoate

20% palladium hydroxide carbon (110 mg) was added to an ethanol solution (2 mL) of the compound (273 mg) of Reference Example 2. The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere, the reaction mixture was filtered, and then concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (chloroform / methanol) to give the title compound (223 mg).
LC-MS [M + H] ⁺ / Rt (min): 263.9 / 0.368 (Method B); ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.90 (1H, dd, J = 7.9, 12.8 Hz), 7.10 (1H, d, J = 7.9 Hz), 7.05 (1H, d, J = 12.8 Hz), 3.92 (3H, s), 3.39-3.27 (1H, m), 3.08-2.79 (6H, m), 1.99 -1.93 (1H, m), 1.78-1.69 (2H, m), 1.66-1.55 (1H, m), 1.44-1.33 (1H, m).

水素化リチウムアルミニウム（６０．５ｍｇ）のテトラヒドロフラン溶液（５ｍＬ）に参考例３の化合物（２１０ｍｇ）のテトラヒドロフラン溶液（５ｍＬ）を０℃で加えた。氷冷下で１時間撹拌し、水（０．０６１ｍｌ）、続いて１５％水酸化ナトリウム水溶液（０．０６１ｍｌ）、さらに水（０．１８３ｍｌ）を０℃にて加えた。２時間撹拌後、反応混合物をろ過し、減圧濃縮した。残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（１２３ｍｇ）を得た。
LC-MS [M+H]^＋/Rt (min)： 235.9/0.207 (Method B); ¹H-NMR (400 MHz, CDCl₃) δ: 7.37 (1H, dd, J = 7.9, 11.6 Hz), 7.04 (1H, dd, J = 1.5, 7.9 Hz), 6.96 (1H, dd, J = 1.5, 11.6 Hz), 4.72 (2H, s), 3.33-3.23 (1H, m), 3.00-2.76 (6H, m), 1.95-1.90 (1H, m), 1.76-1.68 (2H, m), 1.68-1.56 (1H, m), 1.41-1.31 (1H, m). Reference example 4
[4- (1-azabicyclo [2.2.2] octane-3-yl) -2-fluorophenyl] methanol

A solution of the compound of Reference Example 3 (210 mg) in tetrahydrofuran (5 mL) was added to a solution of lithium aluminum hydride (60.5 mg) in tetrahydrofuran (5 mL) at 0 ° C. The mixture was stirred under ice-cooling for 1 hour, and water (0.061 ml), followed by a 15% aqueous sodium hydroxide solution (0.061 ml) and water (0.183 ml) were added at 0 ° C. After stirring for 2 hours, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (chloroform / methanol) to give the title compound (123 mg).
LC-MS [M + H] ⁺ / Rt (min): 235.9 / 0.207 (Method B); ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.37 (1H, dd, J = 7.9, 11.6 Hz), 7.04 (1H, dd, J = 1.5, 7.9 Hz), 6.96 (1H, dd, J = 1.5, 11.6 Hz), 4.72 (2H, s), 3.33-3.23 (1H, m), 3.00-2.76 (6H, 6H, m), 1.95-1.90 (1H, m), 1.76-1.68 (2H, m), 1.68-1.56 (1H, m), 1.41-1.31 (1H, m).

２，４−ジクロロ−6−メチル−5−ニトロピリミジン（２０ｇ）のテトラヒドロフラン溶液（３２１ｍＬ）にＮ，Ｎ−ジイソプロピルエチルアミン（２４．５ｍＬ）とアンモニア（７．０ｍｏｌ／Ｌメタノール溶液、２０．６ｍＬ）を−１０℃で滴下し、−１０℃で２．５時間攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過後、減圧濃縮し、表題化合物（１７．５ｇ）を得た。
LC-MS [M+H]^＋/Rt (min)： 188.8/0.503 (Method B) Reference example 5
2-Chloro-6-methyl-5-nitropyrimidine-4-amine

N, N-diisopropylethylamine (24.5 mL) and ammonia (7.0 mol / L methanol solution, 20.6 mL) in tetrahydrofuran solution (321 mL) of 2,4-dichloro-6-methyl-5-nitropyrimidine (20 g) Was added dropwise at −10 ° C. and stirred at −10 ° C. for 2.5 hours. 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 sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (17.5 g).
LC-MS [M + H] ⁺ / Rt (min): 188.8 / 0.503 (Method B)

参考例５の化合物（４．６２ｇ）のメタノール溶液（９０ｍＬ）に氷冷下、２８％ナトリウムメトキシド溶液（５．６８ｇ）を加えた後、反応混合物を２時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、クロロホルムにて抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をアセトニトリル（１８ｍL）に懸濁し、還流下で３０分撹拌した後、ろ過し、表題化合物（２．７２ｇ）を得た。
LC-MS [M+H]^＋/Rt (min)： 185.3/0.559 (Method A). Reference example 6
2-Methoxy-6-methyl-5-nitropyrimidine-4-amine

A 28% sodium methoxide solution (5.68 g) was added to a methanol solution (90 mL) of the compound (4.62 g) of Reference Example 5 under ice-cooling, and then the reaction mixture was stirred for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in acetonitrile (18 mL), stirred under reflux for 30 minutes and then filtered to give the title compound (2.72 g).
LC-MS [M + H] ⁺ / Rt (min): 185.3 / 0.559 (Method A).

Reference example 7
A reference example 7 compound was obtained using the corresponding raw material compound according to the method described in reference example 6.

参考例７の化合物（１．８ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に氷冷下、ジメチルアミノピリジン（１１０ｍｇ）と二炭酸ジ−ｔｅｒｔ−ブチル（３．７１ｇ）を加えた。反応混合物を室温に昇温後４時間撹拌した。反応混合物に２０％ナトリウムエトキシド溶液（６．２ｍＬ）を加えさらに１時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、クロロホルムにて抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）にて精製し、表題化合物（２．５４ｇ）を得た。
LC-MS [M+H]^＋/Rt (min)： 299.2/1.035 (Method B); ¹H-NMR (400 MHz, CDCl₃) δ: 9.26 (1H, s), 4.51 (2H, q, J = 7.1 Hz), 2.70 (3H, s), 1.53 (9H, s), 1.43 (3H, t, J = 7.1 Hz). Reference example 8
tert-Butyl (2-ethoxy-6-methyl-5-nitropyrimidine-4-yl) carboxylate

Dimethylaminopyridine (110 mg) and di-tert-butyl dicarbonate (3.71 g) were added to a tetrahydrofuran solution (30 mL) of the compound (1.8 g) of Reference Example 7 under ice-cooling. The reaction mixture was heated to room temperature and then stirred for 4 hours. A 20% sodium ethoxide solution (6.2 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.54 g).
LC-MS [M + H] ⁺ / Rt (min): 299.2 / 1.035 (Method B); ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 9.26 (1H, s), 4.51 (2H, q, J) = 7.1 Hz), 2.70 (3H, s), 1.53 (9H, s), 1.43 (3H, t, J = 7.1 Hz).

Reference example 9
The compound of Reference Example 9 was obtained by using the corresponding raw material compound according to the method described in Reference Example 8.

参考例９の化合物（１ｇ）と３−フルオロ−４−（ヒドロキシメチル）フェニル メタンスルホネート（０．７５ｇ）のトルエン溶液（１０ｍＬ）に１，１‘−アゾビス（Ｎ，Ｎ-ジメチルホルムアミド）（０．７１ｇ）とトリブチルホスフィン（０．８３ｇ）を氷冷下加え，氷冷下６時間攪拌した。反応混合物に水を加え、トルエンで抽出した。有機層を飽和炭酸ナトリウム水溶液、飽和塩化アンモニウム水溶液、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過後、減圧濃縮し、表題化合物（２．６３ｇ）をトリブチルホスフィンオキシドと参考例１１の化合物との混合物として得た。これ以上は精製せず、次の反応に用いた。
LC-MS [M+H]^＋/Rt (min)： 487.3/1.065 (Method B). Reference example 10
4-{[(tert-Butyloxycarbonyl) (2-methoxy-6-methyl-5-nitropyrimidine-4-yl) amino] methyl} -3-fluorophenylmethanesulfonate

1,1'-azobis (N, N-dimethylformamide) (0) in a toluene solution (10 mL) of the compound (1 g) of Reference Example 9 and 3-fluoro-4- (hydroxymethyl) phenylmethanesulfonate (0.75 g). .71 g) and tributylphosphine (0.83 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer was washed with saturated aqueous sodium carbonate solution, saturated aqueous ammonium chloride solution, and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The title compound (2.63 g) was combined with tributylphosphine oxide and the compound of Reference Example 11. Obtained as a mixture of. No further purification was used and it was used in the next reaction.
LC-MS [M + H] ⁺ / Rt (min): 487.3 / 1.065 (Method B).

Reference examples 11 to 13
According to the method described in Reference Example 10, the compounds of Reference Examples 11 to 13 were obtained using the corresponding raw material compounds.

参考例１３の化合物（１．９６ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に（１Ｓ，４Ｓ）−２−ｔｅｒｔ−ブトキシカルボニル−２，５−ジアザビシクロ［２．２．１］ヘプタン（１．２３ｇ）、トリアセトキシ水素化ホウ素ナトリウム（１．４９ｇ）を加え、室温で終夜撹拌した。氷冷下で反応混合物に飽和重層水を加えた後、クロロホルムにて抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（２．５２ｇ）を得た。
LC-MS ([M+H]^＋/Rt (min))： 617.5/0.932 (Method A). Reference example 14
tert-Butyl (1S, 4S) -5-[(4-{[(tert-butoxycarbonyl) (2-ethoxy-6-methyl-5-nitropyrimidine-4-yl) amino] methyl} -3-fluorophenyl ) Methyl] -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate

(1S, 4S) -2-tert-butoxycarbonyl-2,5-diazabicyclo [2.2.1] heptane (1.23 g), tri in a tetrahydrofuran solution (30 mL) of the compound (1.96 g) of Reference Example 13. Sodium acetoxyborohydride (1.49 g) was added and stirred at room temperature overnight. Saturated stratified water was added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (2.52 g).
LC-MS ([M + H] ⁺ / Rt (min)): 617.5 / 0.932 (Method A).

参考例１０の化合物（トリブチルホスフィンと参考例１１の化合物との混合物２．５２ｇ）のトルエン溶液（１０ｍＬ）に氷冷下トリフルオロ酢酸（０．３８ｍＬ）を加え、氷冷下１５分攪拌後、室温で３０分攪拌した。水冷下トリフルオロ酢酸（０．３８ｍＬ）を加え、室温で１．５時間攪拌した。水冷下トリフルオロ酢酸（１．７６ｍＬ）を加え、室温で３時間攪拌した。水冷下トリフルオロ酢酸（１．２６ｍＬ）を加え、室温で１．５時間攪拌した後、攪拌を止め、室温で終夜放置した。反応混合物に水とトルエンを加え濃縮した後、残渣に酢酸エチルを加え分液した。有機層を水、飽和重層水、飽和炭酸ナトリウム水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をエタノールで再結晶し、表題化合物（１．０６ｇ）を得た。
LC-MS [M+H]^＋/Rt (min)： 387.1/0.833 (Method B). Reference example 15
3-Fluoro-4-{[(2-Methoxy-6-methyl-5-nitropyrimidine-4-yl) amino] methyl} phenylmethanesulfonate

Trifluoroacetic acid (0.38 mL) under ice-cooling was added to a toluene solution (10 mL) of the compound of Reference Example 10 (2.52 g of a mixture of tributylphosphine and the compound of Reference Example 11), and after stirring for 15 minutes under ice-cooling, The mixture was stirred at room temperature for 30 minutes. Trifluoroacetic acid (0.38 mL) was added under water cooling, and the mixture was stirred at room temperature for 1.5 hours. Trifluoroacetic acid (1.76 mL) was added under water cooling, and the mixture was stirred at room temperature for 3 hours. Trifluoroacetic acid (1.26 mL) was added under water cooling, and the mixture was stirred at room temperature for 1.5 hours, the stirring was stopped, and the mixture was left at room temperature overnight. Water and toluene were added to the reaction mixture for concentration, and then ethyl acetate was added to the residue to separate the liquids. The organic layer was washed with water, saturated stratified water, saturated aqueous sodium carbonate, and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound (1.06 g).
LC-MS [M + H] ⁺ / Rt (min): 387.1 / 0.833 (Method B).

Reference examples 16-19
According to the method described in Reference Example 15, the compounds of Reference Examples 16 to 19 were obtained using the corresponding raw material compounds. The compound of Reference Example 19 can also be obtained by using the compound of Reference Example 18 according to the method described in Reference Example 2.

参考例１７の化合物（１．６９ｇ）のテトラヒドロフラン溶液（２５ｍＬ）に氷冷下、３８％ホルムアルデヒド溶液（０．３０９ｍｌ）、トリアセトキシ水素化ホウ素ナトリウム（１．０７ｇ）を加えた。その後室温まで昇温し、終夜撹拌した。氷冷下で反応混合物に飽和重層水を加えた後、クロロホルムにて抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（１．７３ｇ）を得た。
LC-MS ([M+H]^＋/Rt (min))： 431.4/0.651 (Method A). Reference example 20
2-ethoxy-N-[(2-fluoro-4-{[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane-2-yl] methyl} phenyl) methyl] -6-Methyl-5-nitropyrimidine-4-amine

A 38% formaldehyde solution (0.309 ml) and sodium triacetoxyborohydride (1.07 g) were added to a tetrahydrofuran solution (25 mL) of the compound (1.69 g) of Reference Example 17 under ice-cooling. Then, the temperature was raised to room temperature, and the mixture was stirred overnight. Saturated stratified water was added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (chloroform / methanol) to give the title compound (1.73 g).
LC-MS ([M + H] ⁺ / Rt (min)): 431.4 / 0.651 (Method A).

参考例１５の化合物（１ｇ）の酢酸エチル（８ｍＬ）溶液に室温下、７，７，８，８−テトラシアノキノジメタン（５．３ｍｇ）と１０％パラジウム炭素（０．１ｇ）を加えた。反応混合物を常圧の水素雰囲気下、室温で７時間撹拌した。エタノール（８ｍＬ）を加え、常圧の水素雰囲気下、室温で８時間撹拌した後、反応溶液をセライトろ過し、ろ液を減圧濃縮し、表題化合物（０．９９ｇ）を得た。
LC-MS [M+H]^＋/Rt (min): 357.1/0.414 (Method B). Reference example 21
4-{[(5-Amino-2-methoxy-6-methylpyrimidine-4-yl) amino] methyl} -3-fluorophenylmethanesulfonate

7,7,8,8-Tetracyanoquinodimethane (5.3 mg) and 10% palladium carbon (0.1 g) were added to a solution of the compound (1 g) of Reference Example 15 in ethyl acetate (8 mL) at room temperature. .. The reaction mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere at normal pressure. Ethanol (8 mL) was added, and the mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere at normal pressure, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.99 g).
LC-MS [M + H] ⁺ / Rt (min): 357.1 / 0.414 (Method B).

Reference examples 22 to 24
According to the method described in Reference Example 21, the compounds of Reference Examples 22 to 24 were obtained using the corresponding raw material compounds.

参考例２１の化合物（３．５ｇ）のメタノール（１４ｍＬ）／テトラヒドロフラン（１４ｍＬ）溶液に、氷冷下５ｍｏｌ／Ｌ水酸化ナトリウム水溶液（９．８ｍＬ）を加え、常温で２．５時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液と飽和食塩水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し、ろ過後、溶媒を減圧留去した。得られた残査に酢酸エチルを加え、８５℃下３０分攪拌し、常温まで冷却後、固体をろ取し、表題化合物（１．９８ｇ）を得た。
LC-MS [M+H]^＋ /Rt (min)： 279.1/0.355 (Method B)
参考例２６〜２８
参考例２５に記載の方法に準じ、対応する原料化合物を用いて、参考例２６〜２８の化合物を得た。

Reference example 25
4-{[(5-Amino-2-methoxy-6-methylpyrimidine-4-yl) amino] methyl} -3-fluorophenol

A 5 mol / L sodium hydroxide aqueous solution (9.8 mL) was added to a solution of the compound (3.5 g) of Reference Example 21 in methanol (14 mL) / tetrahydrofuran (14 mL), and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous ammonium chloride solution and a saturated brine were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was stirred at 85 ° C. for 30 minutes, cooled to room temperature, and the solid was collected by filtration to give the title compound (1.98 g).
LC-MS [M + H] ⁺ / Rt (min): 279.1 / 0.355 (Method B)
Reference examples 26-28
According to the method described in Reference Example 25, the compounds of Reference Examples 26 to 28 were obtained using the corresponding raw material compounds.

参考例２６の化合物（１１６ｍｇ）のクロロホルム溶液（２ｍＬ）にＥＤＣＩ・ＨＣｌ（１７３ｍｇ）、ＨＯＢｔ（１２２ｍｇ）、３−フルオロフェニル酢酸（１３９ｍｇ）、ジイソプロピルエチルアミン（０．３１ｍＬ）を加え、室温で３．５時間撹拌した後、終夜静置した。反応混合物を直接シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物を１−［３−（ジメチルアミノ）プロピル］−３−エチルウレアとの混合物（２７２ｍｇ）として得た。これ以上の精製は行わず、次の反応に進めた。
LC-MS ([M+H]^＋/Rt (min))： 524.2/0.468 (Method B) Reference example 29
(S) -N- (4-{[2-fluoro-4- (quinuclidine-3-yloxy) benzyl] amino} -2-methoxy-6-methylpyrimidine-5-yl) -2- (3-fluorophenyl) ) Acetamide

EdCI-HCl (173 mg), HOBt (122 mg), 3-fluorophenylacetic acid (139 mg), and diisopropylethylamine (0.31 mL) were added to a chloroform solution (2 mL) of the compound (116 mg) of Reference Example 26, and 3. After stirring for 5 hours, the mixture was allowed to stand overnight. The reaction mixture was directly purified by silica gel column chromatography (chloroform / methanol) to give the title compound as a mixture (272 mg) with 1- [3- (dimethylamino) propyl] -3-ethylurea. No further purification was performed and the next reaction proceeded.
LC-MS ([M + H] ⁺ / Rt (min)): 524.2 / 0.468 (Method B)

Reference example 30-31
According to the method described in Reference Example 29, the compounds of Reference Examples 30 to 31 were obtained using the corresponding raw material compounds.

Next, the pharmacological action of a typical compound of the present invention will be specifically described with reference to Test Examples.
Test Example 1: Human TLR7 activation inhibition test The human TLR7 expression cell line is a human fetal kidney cell line containing the human TLR7 gene and the secretory alkaline phosphatase (SEAP) gene downstream of the transcription response sequence of NF-κB. A cell line stably expressed in HEK293 was obtained by purchasing from IMGENEX (TLR7 / NF-κB / SEAPorter ^TM HEK293 cells). TLR7 / NF-κB / SEAPorter ^TM HEK293 cells were cultured in DMEM medium containing 10% fetal bovine serum (FBS) and 10 μg / mL Blasticidin S at 37 ° C. in the presence of _{5% CO 2.} The ^{TLR7 / NF-κB / SEAPorter TM} HEK293 cells were seeded in 96-well microtiter plates in ^{5 × 10 4 / 90μL / well} , 37 ℃ in CO ₂ incubator, and cultured overnight. The test compound (10 μL / well) diluted with the medium was added and the final concentrations were 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 μmol / L, or It was set to 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100 μmol / L. After 0.5 hours, the TLR7 / 8 ligand R-848 was added to a final concentration of 200 nmol / L (10 μL / well). SEAP activity was measured as TLR7 activity after incubation in a _{CO 2} incubator for 20 ± 1 hours at a total of 110 μL / well. For SEAP activity, 50 μL / well of p-nitro-phenyl phosphate (pNPP) (Invitrogen) was added, and after 15 minutes, 50 μL / well of 4 mol / L sodium hydroxide solution (Nacalai Tesque) was added to stop the reaction. The absorbance at 405 nm was measured and evaluated with a microplate reader Elx808 (BioTek). _{The 50% inhibitory concentration (IC 50} value) of each test compound was calculated with the SEAP activity when no test compound was added as 100%.

Each compound obtained in Example was subjected to the test shown in Test Example 1. It is shown as follows; the concentration inhibiting 50% cell growth of each test substance (μmol / L _{IC 50} value).

The compound of the present invention showed a strong TLR7 inhibitory effect in the TLR7 activation inhibition test. The compounds of Examples 1, 4, 19, 20, 21, 23, 25, 26 and 29 showed a particularly strong TLR7 inhibitory effect.

Test Example 2: Human TLR8 activation inhibition test The human TLR8 expression cell line is a human fetal kidney cell line containing the human TLR8 gene and the secretory alkaline phosphatase (SEAP) gene downstream of the transcription response sequence of NF-κB. It is obtained by purchasing a cell line stably expressed in HEK293 from IMGENEX (TLR8 / NF-κB / SEAPorter ^TM HEK293 cells). TLR8 / NF-κB / SEAPorter ^TM HEK293 cells are cultured in DMEM medium containing 10% fetal bovine serum (FBS), 10 μg / mL Blasticidin S, at 37 ° C. in the presence of _{5% CO 2.} The ^{TLR8 / NF-κB / SEAPorter TM} HEK293 cells were seeded in 96-well microtiter plates at ^{5 × 10 4 / 90μL / well} , 37 ℃ in CO ₂ incubator and cultured overnight. The test compound (10 μL / well) diluted with the medium is added to adjust the final concentration to 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100 μmol / L. After 0.5 hours, the TLR7 / 8 ligand R-848 is added to a final concentration of 30 μmol / L (10 μL / well). SEAP activity is measured as TLR8 activity after incubation in a _{CO 2} incubator for 20 ± 1 hours at a total of 110 μL / well. For SEAP activity, 50 μL / well of p-nitro-phenyl phosphate (pNPP, Invitrogen) was added, and after 15 minutes, 50 μL / well of 4 mol / L sodium hydroxide solution (Nacalai Tesque) was added to stop the reaction, and the reaction was stopped. It is evaluated by measuring the absorbance at 405 nm with a plate reader Elx808 (BioTek). _{The 50% inhibitory concentration (IC 50} value) of each test compound is calculated with the SEAP activity when no test compound is added as 100%.

Test Example 3: Human TLR9 activation inhibition test The human TLR9 expression cell line is a human fetal kidney cell line containing the human TLR9 gene and the secretory alkaline phosphatase (SEAP) gene downstream of the transcription response sequence of NF-κB. It is obtained by purchasing a cell line stably expressed in HEK293 from IMGENEX (TLR9 / NF-κB / SEAPalter ^TM HEK293 cells). TLR9 / NF-κB / SEAPorter ^TM HEK293 cells are cultured in DMEM medium containing 10% fetal bovine serum (FBS), 10 μg / mL Blastsaidin S, at 37 ° C. in the presence of _{5% CO 2.} The ^{TLR9 / NF-κB / SEAPorter TM} HEK293 cells were seeded in 96-well microtiter plates at ^{5 × 10 4 / 90μL / well} , 37 ℃ in CO ₂ incubator and cultured overnight. The test compound (10 μL / well) diluted with the medium is added to obtain final concentrations of 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, and 100 μmol / L. After 0.5 hours, the TLR9 ligand CpG-B DNA (CpG2006, Hokkaido System Science) is added to a final concentration of 500 nmol / L (10 μL / well). SEAP activity is measured as TLR9 activity after incubation in a _{CO 2} incubator for 20 ± 1 hours at a total of 110 μL / well. For SEAP activity, 50 μL / well of p-nitro-phenyl phosphate (pNPP) (Invitrogen) was added, and after 15 minutes, 50 μL / well of 4 mol / L sodium hydroxide solution (Nacalai Tesque) was added to stop the reaction. It is evaluated by measuring the absorbance at 405 nm with a microplate reader Elx808 (BioTek). _{The 50% inhibitory concentration (IC 50} value) of each test compound is calculated with the SEAP activity when no test compound is added as 100%.

As described above, the compound of the present invention has a TLR inhibitory effect and is therefore useful for the prevention and / or treatment of autoimmune diseases.

Claims (26)

Equation (1):

[In the formula, R ¹ is _{optionally substituted C 1-6} alkoxy, optionally substituted C _3-7 cycloalkoxy, optionally substituted 4- to 7-membered saturated heterocyclic group- oxy, optionally substituted C _1-6 alkyl, optionally substituted C _3-7 cycloalkyl, optionally substituted C _1-6 alkylthio, 4 may be substituted 7-membered Represents a saturated heterocyclic group, optionally substituted amino, or halogen atom;
R ² represents _{an optionally substituted C 1-6} alkyl, _{an optionally substituted C 3-7} cycloalkyl, or an optionally substituted amino;
W ¹ represents a _{C 1-4} alkylene that may be single bond or substituted;
Ring ^{Q 1} is _represents a _{C 6-10} aryl or a 5- to 10-membered heteroaryl;
n represents 1, 2, 3 or 4;
If there are a plurality of R ³ , hydrogen atom, halogen atom, cyano, hydroxy, C _1-6 alkyl which may be _{substituted, C 1-6} alkoxy which may be substituted, and substituted. also represent an optionally C _3-7 cycloalkyl, optionally substituted C _3-7 cycloalkoxy, or amino which may be substituted;
Q ^1- X ¹ is Q ¹ -single bond, Q ^1- (CH ₂ ) _m- O-, Q ^1- (CH ₂ ) _m -S-, Q ^1- (CH ₂ ) _m- S (O) ₂ −, Q ¹ − (CH ₂ ) _m −NR ^a S (O) ₂ −, Q ¹ − (CH ₂ ) _m − S (O) ₂ NR ^a −, Q ¹ − (CH ₂ ) _m −C ( O) −, Q ¹ − (CH ₂ ) _m −NR ^a −, Q ¹ − (CH ₂ ) _m −NR ^a C (O) −, or Q ¹ − (CH ₂ ) _{m −} C (O) NR ^a -(Here, ^Ra represents a hydrogen atom or C _1-6 alkyl; m represents 0, 1 or 2);
W ² represents a _{C 1-8} alkylene that may be single bonded or substituted;
R ⁴ is −OR ^b (where R ^b is a hydrogen atom, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkyl carbonyl, optionally substituted amino. Carbonyl, or optionally substituted C _1-6 alkyl sulfonyl), -NR ^c R ^d (where R ^c represents hydrogen atom or optionally substituted C _1-6 alkyl; R ^d is a hydrogen atom, an optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkylcarbonyl, optionally substituted C _1-6 alkoxycarbonyl, or optionally substituted Represents a good C _1-6 alkylsulfonyl), or represents a 4- to 10-membered saturated heterocyclic group that may be substituted;
X ^2- R ⁵ is a single bond,-(CH ₂ ) _k- C (O) -R ⁵ , or-(CH ₂ ) _k- C (O) NR ^e- R ⁵ (where ^Re is Represents a hydrogen atom or an optionally substituted C _1-6 alkyl; k represents 0, 1 or 2);
R ⁵ is C _1-6 alkoxy which may be _{substituted, C 1-8} alkyl which may be _{substituted, C 3-12 cycloalkyl which may be substituted, C 6-} which may be substituted. ₁₀ aryl, saturated heterocyclic group of a 4 membered to 10-membered optionally substituted or an heteroaryl which may be substituted 5-membered optionally 10-membered, with the proviso, R ⁵ is an optionally substituted C _6-10 when it is aryl or substituted optionally 5-membered to 10-membered be heteroaryl, X ² -R ⁵ is a compound represented by] not a single bond -R ^5, or a pharmaceutically acceptable, Salt to be done. R ¹
(1) C _1-6 Alkoxy, (the group is
(A) Halogen atom,
(B) Hydroxy,
(C) C _1-6 alkoxy (the group may be substituted with the same or different 1-3 halogen atoms),
(D) C _3-7 cycloalkyl (the group is substituted with 1 to 4 similar or heterologous groups selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(E) C _3-7 cycloalkoxy (the group is substituted with 1 to 4 similar or heterologous groups selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(F) Phenyl (the group may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy),}
(G) 5- or 6-membered heteroaryl (the group is substituted with 1 to 4 groups of the same or different species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} (May be), and (h) a 4- to 7-membered saturated heterocyclic group of the same species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} It may be substituted with 1 to 4 different groups)
It may be substituted with 1-3 groups of the same or different species selected from the group consisting of),
(2) C _3-7 cycloalkoxy, (the group is substituted with 1 to 4 groups of the same or different type selected from the group consisting of halogen atom, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(3) 4- to 7-membered saturated heterocyclic group-oxy (the group is 1 to 4 of the same or different species selected from the group _{consisting of halogen atom, C 1-6} alkyl, and C _{1-6 alkoxy.} May be replaced with a group of),
(4) C _1-6 alkyl (the group may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy),}
(5) C _3-7 cycloalkyl (the group is substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(6) C _1-6 alkylthio (the group may be substituted with the same or different 1 to 3 halogen atoms),
(7) 4- to 7-membered saturated heterocyclic groups (the groups are 1 to 4 groups of the same or different species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} May be replaced with),
(8) Amino (the group may be substituted with the same or different 1-2 C _1-6 alkyls (the group may be substituted with the same or different 1-3 halogen atoms). May be), or (9) a halogen atom;
R ² _{is, C 1-6} alkyl (said group may be substituted by same or different 1 to 3 halogen _{atoms), C 3-7} cycloalkyl or amino (in which, is identical or different It may be substituted with 1-2 C _{1-6 alkyls);}
W ¹ is a single bond or _{C 1-4} alkylene (said groups, halogen atoms, hydroxy, and _{C 1-6} optionally substituted with 1-4 groups of same or different selected from the group consisting of alkoxy May be);
Ring ^{Q 1} is _located at _{C 6-10} aryl or a 5- to 10-membered heteroaryl;
n is 1, 2, 3 or 4;
R ³ is, if there are a plurality of independently,
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) With C _1-6 alkyl (the group may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy).} May have been replaced),
(6) C _1-6 alkoxy (the group may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy),}
(7) C _3-7 cycloalkyl (the group is substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(8) C _3-7 cycloalkoxy (the group is substituted with 1 to 4 groups of the same or different type selected from the group consisting of halogen atom, C _1-6 alkyl, and C _{1-6 alkoxy.} (May be), or (9) amino (the group may be substituted with the same or different 1-2 C _1-6 alkyl (the group may be substituted with the same or different 1-3 halogen atoms). ) May be replaced);
Q ¹ -X ¹ - is, ^{Q 1} - single bond _{^{-, Q 1 - (CH 2}} ) m -O-, Q 1 - (CH 2) m -S-, Q 1 - (CH 2) m -S ( O) ₂ −, Q ¹ − (CH ₂ ) _m −NR ^a S (O) ₂ −, Q ¹ − (CH ₂ ) _m − S (O) ₂ NR ^a −, Q ¹ − (CH ₂ ) _m − C (O)-, Q ^1- (CH ₂ ) _m- NR ^a- , Q ^1- (CH ₂ ) _m- NR ^a C (O)-, or Q ^1- (CH ₂ ) _m- C (O) NR ^a − (where ^Ra is a hydrogen atom or C _1-6 alkyl; m is 0, 1 or 2);
W ² represents a _{C 1-8} alkylene that may be single bonded or substituted;
R ⁴
(1) -OR ^b (where R ^b is a hydrogen atom, C _1-6 alkyl, C _1-6 alkyl carbonyl, mono- or di-C _1-6 alkyl-aminocarbonyl, or C _1-6 alkyl (Sulfonyl),
(2) -NR ^c R ^d (where R ^c is a hydrogen atom or C _1-6 alkyl (the group may be substituted with the same or different 1-3 halogen atoms); R ^d is a hydrogen atom, C _1-6 alkyl (the group may be a halogen atom, hydroxy, amino (the group may be substituted with _{one or two C 1-6 alkyls of the same or different),} And C _1-6 alkylcarbonyl (which may be substituted with 1-3 groups of the same or different species selected from the group consisting of _{C 1-6 alkoxy), C 1-6} alkylcarbonyl (where the groups are halogen atoms, hydroxy, amino ( The groups may be substituted with the same or different 1-2 C _1-6 alkyls), and 1-3 groups of the same or different species selected from the group consisting of _{C 1-6 alkoxy.} (May be substituted), C _1-6 alkoxycarbonyl, or C _1-6 alkylsulfonyl), or (3) 4- or 10-membered saturated heterocyclic groups (the groups are:
(A) Halogen atom,
(B) Hydroxy,
(C) Cyano,
(D) C _1-6 alkyl (the group may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy),}
(E) C _1-6 alkoxy (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy),}
(F) C _3-7 cycloalkyl,
(G) C _1-6 alkylcarbonyl (the group may be substituted with a halogen atom, hydroxy, amino (the group may be substituted with the same or different 1-2 C _1-6 alkyls), and C ₁ It may be substituted with 1-3 groups of the same or different species selected from the group consisting of _{-6 alkoxy),}
(H) C _1-6 alkoxycarbonyl,
(I) 4- to 7-membered saturated heterocyclic groups (the groups are 1 to 4 homologous or heterologous groups selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} May be replaced with),
(J) Phenyl (the group may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy),.}
(K) 5- or 6-membered heteroaryl (the group is substituted with 1 to 4 groups of the same or different species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} It may be), and (l) it may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of oxo);
X ^2- R ⁵ is a single bond -R ⁵ ,-(CH ₂ ) _k- C (O) -R ⁵ ,-(CH ₂ ) _k- C (O) NR ^e- R ⁵ (here, ^Re Represents a hydrogen atom or C _1-6 alkyl (the group may be substituted with the same or different 1-3 halogen atoms), or ^Re and R ⁵ are alkyl at the same time. when, saturated Hajime Tamaki (in which the 4-membered to 7-membered together with the nitrogen atom to which R ^e and R ⁵ are attached may be homologous are selected from halogen atoms, and the group consisting of C _1-6 alkyl, or It may be substituted with 1-3 different groups); k represents 0, 1 or 2);
R ⁵
(1) C _1-6 alkoxy, (the group may be substituted with the same or different 1 to 3 halogen atoms).
(2) C _1-8 alkyl (the group is
(A) Halogen atom,
(B) Cyano (c) Hydroxy,
(D) C _1-6 alkoxy (the group may be substituted with the same or different 1-3 halogen atoms),
(E) C _3-7 cycloalkyl (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(F) C _3-7 cycloalkoxy (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(G) Amino (the group is a C _1-6 alkyl (the group is a homologous or heterologous 1-3 group selected from the group consisting of a halogen atom, a cyano, a hydroxy, and a C _{3-7 cycloalkyl). (May} be substituted with), C 3-7 cycloalkyl, C _1-6 alkyl sulfonyl, and C _1-6 alkyl carbonyl substituted with 1 to 4 groups of the same or different species selected from the group. May be),
(H) C _1-6 alkylsulfonyl (the group may be substituted with the same or different 1-3 halogen atoms),
(I) C _6-10 aryl (the groups are halogen atoms, cyano, hydroxy, amino, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, and C _1- It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of _{6 alkylsulfonyls),}
(J) 5- or 6-membered heteroaryl (the groups are halogen atoms, cyanos, C _1-6 alkyls, C _1-6 alcohols, mono- or di-C _1-6 alkylaminos, and C _1-6. It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of alkylsulfonyls), and (k) 4- to 7-membered saturated heterocyclic groups (where the groups are halogen atoms, Cyan, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, C _1-6 alkyl sulfonyl, C _1-6 alkyl carbonyl, and mono- or di-C _{1 It} may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of -6 alkylaminocarbonyl).
It may be substituted with 1-3 groups of the same or different species selected from the group consisting of),
(3) C _3-12 cycloalkyl (the group is halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, C _1-6 alkyl It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of sulfonyls and mono- or di-C _{1-6 alkylaminocarbonyls),}
(4) C _3-7 cycloalkoxy (the group is 1 to 4 groups of the same type or different from each other selected from the group consisting of halogen atom, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with)
(5) C _6-10 aryl (the groups are halogen atoms, cyano, hydroxy, amino, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, and C _1- It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of _{6 alkylsulfonyls),}
(6) 4-membered to 10-membered saturated heterocyclic group (the group is a halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkylamino, C. _It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1-6 alkylsulfonyl, C _1-6 alkylcarbonyl, and mono- or di-C _{1-6 alkylaminocarbonyl.} ), Or (7) 5- to 10-membered heteroaryl (the groups are halogen atoms, cyano, C _1-6 alkyl, C _1-6 alcohol, mono- or di-C _1-6 alkylamino, and C. It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of _{1-6 alkylsulfonyls).}
However, when R ⁵ is a _{optionally substituted C 6-10} aryl or an optionally substituted 5- to 10-membered heteroaryl, X ^2- R ⁵ is not a single bond-R ^5.
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. R ¹
(1) C _1-6 Alkoxy, (the group is
(A) Halogen atom,
(B) Hydroxy,
(C) C _1-6 alkoxy (the group may be substituted with the same or different 1-3 halogen atoms),
(D) C _3-7 cycloalkyl (the group is substituted with 1 to 4 similar or heterologous groups selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(E) C _3-7 cycloalkoxy (the group is substituted with 1 to 4 similar or heterologous groups selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy.} May be),
(F) Phenyl (the group may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy),}
(G) 5- or 6-membered heteroaryl (the group is substituted with 1 to 4 groups of the same or different species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} (May be), and (h) a 4- to 7-membered saturated heterocyclic group of the same species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} It may be substituted with 1 to 4 different groups)
It may be substituted with 1-3 groups of the same or different species selected from the group consisting of),
(2) C _3-7 cycloalkoxy (the group is substituted with 1 to 4 groups of the same or different type selected from the group consisting of halogen atom, C _1-6 alkyl, and C _{1-6 alkoxy.} Or (3) a 4- to 7-membered saturated heterocyclic group-oxy (the group is of the same species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy).} The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which may be substituted with 1 to 4 different groups). R ¹
(1) C _1-6 alkoxy (the group is the same species selected from the group consisting of halogen atom, hydroxy, C _1-6 alkoxy, C _3-7 cycloalkyl, and 4- to 7-membered saturated heterocyclic groups. Alternatively, it may be substituted with 1 to 3 different groups), or (2) a 4- to 10-membered saturated heterocyclic group-oxy (the group consists of a halogen atom and a C _1-6 alkyl). The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, which may be substituted with 1 to 4 groups of the same type or different types selected from the group. .. Claims 1-4, wherein R ² is C _1-6 alkyl (the group may be substituted with the same or different 1-3 halogen atoms), C _3-7 cycloalkyl, or amino. The compound according to any one of the above or a pharmaceutically acceptable salt thereof. Salts R ² is C _1-6 alkyl or amino, is a compound or a pharmaceutically acceptable according to any one of claims 1 to 5. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein W ¹ _{is C 1-4 alkylene.} Ring Q ¹ is a benzene ring or a 5- or 6-membered aromatic heterocyclic group, A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7. The compound according to any one of claims 1 to 8, wherein n is 1 or 2, or a pharmaceutically acceptable salt thereof. R ³ is independently each if plural, hydrogen atom, halogen atom, hydroxy, C _1-6 alkyl (this group may be substituted by same or different 1 to 3 halogen atoms), Alternatively, the compound according to any one of claims 1 to 9, which is C _1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms) or a pharmaceutical product thereof. Tolerable salt. Q ^1- X ¹ is Q ¹ -single bond, Q ^1- (CH ₂ ) _m- O-, Q ^1- (CH ₂ ) _m- C (O)-, Q ^1- (CH ₂ ) _m- NR ^a − or Q ¹ − (CH ₂ ) _{m −} C (O) NR ^a − (where ^Ra is a hydrogen atom or C _1-6 alkyl; m is 0, 1 or 2) The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein W ² is a single bond or C _{1-8 alkylene.} R ⁴
(1) -OR ^b (where R ^b represents C _1-6 alkyl or C _1-6 alkyl sulfonyl),
(2) -NR ^c R ^d (where R ^c and R ^d are independently substituted with a hydrogen atom or a C _1-6 alkyl (the group is substituted with the same or different 1 to 3 halogen atoms, respectively). (May be), or (3) a 4-membered to 10-membered saturated heterocyclic group (the group is
(A) Halogen atom,
(B) Hydroxy,
(C) C _1-6 alkyl (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy),}
(D) C _1-6 alkoxy (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy),}
(E) C _3-7 cycloalkyl,
(F) C _1-6 alkylcarbonyl (the group may be substituted with a halogen atom, hydroxy, amino (the group may be substituted with the same or different 1-2 C _1-6 alkyls), and C ₁ It may be substituted with 1-3 groups of the same or different species selected from the group consisting of _{-6 alkoxy),}
(G) C _1-6 Alkoxycarbonyl,
(H) 4- to 7-membered saturated heterocyclic group (the group is 1 to 4 homologous or heterologous groups selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} (May be substituted with 1 to 4 groups of the same or different species selected from the group consisting of oxo)), any of claims 1-12. The compound according to paragraph 1 or a pharmaceutically acceptable salt thereof. ^{Claims 1 to 5} , wherein X ^2- R ⁵ is a single bond -R _{5 or-(CH 2} ) _k- C (O) -R ⁵ (where k represents 0, 1 or 2). 13. The compound according to any one of 13 or a pharmaceutically acceptable salt thereof. R ⁵
(1) C _1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms),
(2) C _1-8 alkyl, (the group is
(A) Halogen atom,
(B) Cyano (c) Hydroxy,
(D) C _1-6 alkoxy (the group may be substituted with the same or different 1-3 halogen atoms),
(E) C _3-7 cycloalkyl (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(F) C _3-7 cycloalkoxy (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(G) Amino (the group is a C _1-6 alkyl (the group is a homologous or heterologous 1-3 group selected from the group consisting of a halogen atom, a cyano, a hydroxy, and a C _{3-7 cycloalkyl). (May} be substituted with), C 3-7 cycloalkyl, C _1-6 alkyl sulfonyl, and C _1-6 alkyl carbonyl substituted with 1 to 4 groups of the same or different species selected from the group. May be),
And (h) C _1-6 alkylsulfonyl (the group may be substituted with the same or different 1-3 halogen atoms).
It may be substituted with 1-3 groups of the same or different species selected from the group consisting of),
(3) C _3-12 cycloalkyl (the group is halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, C _1-6 alkyl It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of sulfonyls and mono- or di-C _{1-6 alkylaminocarbonyls),}
(4) C _3-7 cycloalkoxy (the group is 1 to 4 groups of the same type or different from each other selected from the group consisting of halogen atom, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with)
(5) C _6-10 aryl (the groups are halogen atoms, cyano, hydroxy, amino, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, and C _1- It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of _{6 alkylsulfonyls),}
(6) 4-membered to 10-membered saturated heterocyclic group (the group is a halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, C. _It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1-6 alkylsulfonyl, C _1-6 alkylcarbonyl, and mono- or di-C _{1-6 alkylaminocarbonyl.} ), Or (7) 5- to 10-membered heteroaryl (the groups are halogen atoms, cyanos, C _1-6 alkyls, C _1-6 alcohols, mono- or di-C _1-6 alkylaminos, and C. _It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1-6 alkylsulfonyls)
The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof. Equation (1a):

[In the formula, R ¹¹ is
(1) C _1-6 alkoxy (the group is the same or the same selected from the group consisting of halogen atom, hydroxy, C _1-6 alkoxy, C _{3-7 cycloalkyl and 4- to 7-membered saturated heterocyclic groups.} It may be substituted with 1 to 3 different groups),
(2) 4- to 10-membered saturated heterocyclic group-oxy (the group is substituted with 1 to 4 groups of the same or different species selected from the group consisting of _{halogen atoms and C 1-6 alkyl.} May be);
R ¹² represents C _1-6 alkyl, or amino;
Ring Q ¹¹ represents a benzene ring or a 5- or 6-membered aromatic heterocyclic group;
R ^13, when there are a plurality of independently,
(1) Hydrogen atom,
(2) Halogen atom,
(3) Hydroxy,
(4) C _1-6 alkyl (the group may be substituted with the same or different 1-3 halogen atoms), or (5) C _1-6 alkoxy (the group is the same or different 1). Represents (may be substituted with ~ 3 halogen atoms);
Q ¹¹ -X ¹¹ - ^{is, Q 11} - single bond _{^{-, Q 11 - (CH 2}} ) m -O-, Q 11 - (CH 2) m -C (O) -, Q 11 - (CH 2) m −NR ^a −, or Q ¹¹ − (CH ₂ ) _m −C (O) NR ^a − (where ^Ra represents a hydrogen atom or C _1-6 alkyl; m represents 0, 1 or 2 Represent) Represent;
W ¹² represents a single bond or C _1-3 alkylene;
R ¹⁴ is
(1) -OR ^b (where R ^b represents C _1-6 alkyl or C _1-6 alkyl sulfonyl),
(2) -NR ^c R ^d (where R ^c and R ^d are independently substituted with a hydrogen atom or a C _1-6 alkyl (the group is substituted with the same or different 1 to 3 halogen atoms, respectively). Represents),
(3) 4-membered to 10-membered saturated heterocyclic group (the group is
(A) Halogen atom,
(B) Hydroxy,
(C) C _1-6 alkyl (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy),}
(D) C _1-6 alkoxy (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy),}
(E) C _3-7 cycloalkyl,
(F) C _1-6 alkylcarbonyl (the group may be substituted with a halogen atom, hydroxy, amino (the group may be substituted with the same or different 1-2 C _1-6 alkyls), and C ₁ It may be substituted with 1-3 groups of the same or different species selected from the group consisting of _{-6 alkoxy),}
(G) C _1-6 Alkoxycarbonyl,
(H) A 4- to 7-membered saturated heterocyclic group (the group is a homologous or heterologous 1 to 4 group selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} (May be substituted with 1 to 4 groups of the same or different species selected from the group consisting of oxo));
X ^12- R ¹⁵ is a single bond, _{or-(CH 2} ) _k- C (O) -R ¹⁵ (where j represents 1 or 2; k represents 0, 1 or 2). Representation;
R ¹⁵ is,
(1) C _1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms),
(2) C _1-8 alkyl, (the group is
(A) Halogen atom,
(B) Cyano (c) Hydroxy,
(D) C _1-6 alkoxy (the group may be substituted with the same or different 1-3 halogen atoms),
(E) C _3-7 cycloalkyl (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(F) C _3-7 cycloalkoxy (where the groups are 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with),
(G) Amino (the group is a C _1-6 alkyl (the group is a homologous or heterologous 1-3 group selected from the group consisting of halogen atoms, cyanos, hydroxys, and C _{3-7 cycloalkyls). (May} be substituted with), C 3-7 cycloalkyl, C _1-6 alkyl sulfonyl, and C _1-6 alkyl carbonyl substituted with 1 to 4 groups of the same or different species selected from the group. May be)
, And (h) C _1-6 alkylsulfonyl (the group may be substituted with the same or different 1-3 halogen atoms).
It may be substituted with 1-3 groups of the same or different species selected from the group consisting of),
(3) C _3-12 cycloalkyl (the group is halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, C _1-6 alkyl It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of sulfonyls and mono- or di-C _{1-6 alkylaminocarbonyls),}
(4) C _3-7 cycloalkoxy (the group is 1 to 4 groups of the same type or different from each other selected from the group consisting of halogen atom, cyano, hydroxy, C _1-6 alkyl, and C _{1-6 alkoxy.} May be replaced with)
(5) C _6-10 aryl (the groups are halogen atoms, cyano, hydroxy, amino, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, and C _1- It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of _{6 alkylsulfonyls),}
(6) 4-membered to 10-membered saturated heterocyclic group (the group is a halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkyl amino, C. _It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1-6 alkylsulfonyl, C _1-6 alkylcarbonyl, and mono- or di-C _{1-6 alkylaminocarbonyl.} ), Or (7) 5- to 10-membered heteroaryl (the group is a halogen atom, cyano, C _1-6 alkyl, C _1-6 alcohol, mono- or di-C _1-6 alkylamino, C _{1). It} may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of -6 alkylsulfonyl)
However, when R ¹⁵ is a _{optionally substituted C 6-10} aryl or an optionally substituted 5- to 10-membered heteroaryl, X ^12- R ¹⁵ is a single bond-R ¹⁵ . No], or a pharmaceutically acceptable salt thereof. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein X ^12- R ¹⁵ is a single bond-R ^15. R ¹¹ is C _1-6 alkoxy (the group may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxy, and C _{1-6 alkoxy).} The compound according to claim 16 or 17, or a pharmaceutically acceptable salt thereof. R ¹⁴
(1) -NR ^c R ^d (where R ^c and R ^d are independently substituted with a hydrogen atom or a C _1-6 alkyl (the group is substituted with the same or different 1 to 3 halogen atoms, respectively). (May be), or (2) a 4-membered to 10-membered nitrogen-containing saturated heterocyclic group (the group is
(A) Halogen atom,
(B) Hydroxy,
(C) C _1-6 alkyl (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy),}
(D) C _1-6 alkoxy (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy),}
(E) C _3-7 cycloalkyl,
(F) C _1-6 alkylcarbonyl (the group may be substituted with a halogen atom, hydroxy, amino (the group may be substituted with the same or different 1-2 C _1-6 alkyls), and C ₁ It may be substituted with 1-3 groups of the same or different species selected from the group consisting of _{-6 alkoxy),}
(G) C _1-6 Alkoxycarbonyl,
(H) A 4- to 7-membered saturated heterocyclic group (the group is a homologous or heterologous 1 to 4 group selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of (i) oxo).
The compound according to any one of claims 16 to 18, or a pharmaceutically acceptable salt thereof. A medicament containing the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic agent for an autoimmune disease, which comprises the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof as an active ingredient. A TLR7 inhibitor containing the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof as an active ingredient. Systemic lupus erythematosus, lupus nephritis, Sjogren's syndrome, idiopathic thrombocytopenic purpura, psoriasis containing the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof as an active ingredient. , Rheumatoid arthritis, polymyositis, dermatomyositis, Behcet's disease, polysclerosis, or pemphigus. The compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, and a steroid agent, an immunosuppressant, a B cell targeting agent, a TLR inhibitor, and other autoimmunity. A drug obtained by combining at least one drug selected from disease therapeutic agents. For the manufacture of therapeutic agents for systemic lupus erythematosus, lupus nephritis, Sjogren's syndrome, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, polymyositis, dermatomyositis, Behcet's disease, polysclerosis, or pemphigus. Use of the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof. Systemic lupus erythematosus, lupus nephritis, Sjogren's syndrome in a mammal comprising administering to the mammal an effective amount of the compound according to any one of claims 1-19 or a pharmaceutically acceptable salt thereof. , Treatment of idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, polymyositis, dermatomyositis, Behcet's disease, polysclerosis, or pemphigus.