WO2011136247A1

WO2011136247A1 - Novel heteroaryl monocyclic pyrimidine derivative

Info

Publication number: WO2011136247A1
Application number: PCT/JP2011/060214
Authority: WO
Inventors: 成宏浅野; 学渡邊; 義明磯部
Original assignee: 大日本住友製薬株式会社
Priority date: 2010-04-27
Filing date: 2011-04-27
Publication date: 2011-11-03
Also published as: JP2013147428A

Abstract

Disclosed is a heteroaryl monocyclic pyrimidine derivative which is useful as a drug. Specifically disclosed is a pyrimidine derivative represented by formula (I) which is efficacious in preventing and/or treating diseases relating to signal transmission via Toll-like receptor (TLR). In formula (I), A1 and A2 are represented by formula (A) or (B), provided that when A1 is represented by formula (A), A2 is represented by formula (B), and when A1 is represented by formula (B), A2 is represented by formula (A), [wherein X represents C1-8 alkylene or the like; Y represents a hydrogen atom or the like.; Het represents a 5- or 6-membered nitrogen-containing heteroarylene; W represents C1-8 alkylene or the like; Z1 and Z2 represent a hydrogen atom or the like; Z3 and Z4 represent a hydrogen atom or the like; and R1 to R4 represent a hydrogen atom or the like].

Description

Novel heteroaryl monocyclic pyrimidine derivatives

The present invention relates to a heteroaryl monocyclic pyrimidine derivative useful as a medicine. More specifically, the present invention relates to a heteroaryl monocyclic pyrimidine derivative that is effective for the prevention and / or treatment of diseases associated with signal transduction via a Toll-like receptor (TLR). Specifically, diseases involving autoimmunity (sepsis, inflammation, allergies, asthma, graft rejection, graft-versus-host disease, infections, cancer), immunodeficiencies or neurodegenerative diseases (Alzheimer, Parkinson's disease, etc.) The present invention relates to a heteroaryl monocyclic pyrimidine derivative as a prophylactic and / or therapeutic agent.

Stimulation of the immune system in vivo results in a physiological result that is protective to the host or that is harmful to it. In recent years, interest in these innate immunity (innate immunity) mechanisms has increased. In particular, recently discovered TLRs have been reported to be involved in innate immunity and to be receptors that recognize pathogenic microorganisms. TLRs are highly conserved pattern recognition receptors and are attracting attention. To date, 10 human TLRs have been identified and named TLR ¹ -TLR ¹⁰ . Each TLR discriminates a specific molecular structure (pasogen-associated molecular pattern, PAMPs) typified by cell wall components and DNA of pathogenic microorganisms, induces an immune response of the host, and is responsible for biological defense ( Nature Reviews Immunology, 2001, 1, 135-145). For example, TLR ² transmits signals such as peptidoglycan, which is a component of microbial cell wall, and zymosan of yeast, and TLR ⁴ transmits a signal of lipopolysaccharide (LPS), which is a component of Gram-negative cell wall, from outside the host cell. It is transmitted into cells (Nature Immunology, 2001, 2, 675-680). In addition, TLR ⁹ expressed in endosomes in host cells has been reported to recognize DNA of pathogenic microorganisms and CpG DNA, and has attracted particular attention (Nature, 2000, 408, 740-745 or Proceedings of the National Academy of Sciences, 2001, 98, 9237-9242). Therefore, drugs and / or compositions useful for controlling innate immunity via this TLR are used in the following diseases involving autoimmunity (sepsis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease, Infectious diseases, cancer), immunodeficiencies or neurodegenerative diseases (Alzheimer, Parkinson's disease, etc.) can be prophylactic and / or therapeutic agents.

An “autoimmune disease” is a disease that leads to tissue damage due to the continuous production of antibodies or lymphocytes that react with components that constitute the tissue of the self, and includes the following (1) organ-specific self There are two broad categories: immune diseases and (2) non-organ-specific autoimmune diseases (systemic autoimmune diseases).
(1) Organ-specific autoimmune diseases: Hashimoto's disease, primary myxedema, thyroid poisoning, pernicious anemia, Good-pasture syndrome, acute progressive glomerulonephritis, myasthenia gravis, pemphigus vulgaris, bullous Pemphigus, insulin resistant diabetes, juvenile diabetes, type I diabetes, Addison's disease, atrophic gastritis, male infertility, premature menopause, phakogenic uveitis, multiple sclerosis, ulcerative colitis, primary Biliary cirrhosis, chronic active hepatitis, autoimmune blood diseases (eg, autoimmune hemolytic anemia, idiopathic thrombocytopenia), paroxysmal hemoglobinuria, primary biliary cirrhosis, Guillain-Barre syndrome , Graves' disease, idiopathic thrombocytopenic purpura, interstitial pulmonary fibrosis and chronic discoid lupus erythematosus.
(2) Non-organ-specific autoimmune disease (systemic autoimmune disease): rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, polymyositis, dermatomyositis, systemic sclerosis, polyarteritis nodosa, allergic granulation Seed vasculitis, scleroderma and mixed connective tissue disease.

On the other hand, sepsis is defined as Systemic Inflammatory Response Syndrome (SIRS) (Chest, 1992, 101, 1644-1655). The cause of this is the overproduction of inflammatory mediators induced by pathogenic microorganisms and its toxins. Has been thought to be involved.

In recent years, drugs that suppress inflammatory mediators such as nitric oxide (NO) and cytokines have been developed under these circumstances, and their effectiveness has been demonstrated at the animal level, and inflammatory mediators have been developed for patients with severe sepsis. A clinical trial of targeted drug therapy was conducted. However, sufficient therapeutic effects have not been obtained so far, and it is suggested that high effects cannot be expected just by suppressing some of the inflammatory mediators that form a complex network (British Medical Bulletin, 1999, 55, 212-225). From these results, in recent years, the imbalance between inflammatory mediators and anti-inflammatory mediators expressed by the immune response has been associated with increased sepsis, septic shock, and subsequent onset of organ failure, secondary sepsis. It is thought to be deeply involved in the recurrence of the disease or poor prognosis of sepsis. Therefore, it can be expected that the control of the immune response from the TLR that controls innate immunity will be the fundamental prevention and / or treatment of the above-mentioned sepsis-related diseases. In particular, inhibitors against TLR ⁹ can be expected to selectively control immune responses elicited from pathogenic microorganisms. In addition, TLR ⁹ inhibitors can be expected to have further effects when used alone, in combination with TLR ² inhibitors, in combination with TLR ⁴ inhibitors, or in combination with TLR ² inhibitors and TLR ^4. I can expect. Further effects on sepsis-related diseases can be expected by combination therapy in combination with existing sepsis treatment methods such as existing antibacterial agents and blood coagulants.

Chloroquine (a) developed as an antimalarial drug is also used for the treatment of various autoimmune diseases (such as rheumatoid arthritis and systemic lupus erythematosus), and is also useful as an anti-inflammatory drug. Recently, it has been reported that the mechanism of action of chloroquine and its analog quinacrine (b) against the autoimmune disease is due to TLR ⁹ antagonism (European Journal of Immunology, 2004, 34, 2541-2550). ).

In addition, there is a recent disclosure regarding a TLR ⁹ inhibitor, but the structure is different from the compound of the present invention (Patent Document 1). The following representative compound (c) is also disclosed as a compound having TLR ⁷ , TLR ⁸ and TLR ⁹ antagonism, but the structure is different from the compound of the present invention (Patent Document 2).

International Publication No. 2000/076982 International Publication No. 2008/030455

The object of the present invention is to prevent and / or treat autoimmune diseases, specifically diseases involving autoimmunity (inflammation, allergy, asthma, graft rejection, graft-versus-host disease, infection, cancer), immunity It is to provide preventive and / or therapeutic agents for deficiencies or neurodegenerative diseases (Alzheimer, Parkinson's disease, etc.). Another object of the present invention is to provide a pharmaceutical effective for the prevention and / or treatment of sepsis, particularly severe sepsis, by finding a TLR inhibitor that selectively inhibits TLR.

As a result of intensive studies, the present inventors have found that a novel compound represented by the following formula (I) exhibits a strong TLR inhibitory action and can be a useful drug for the prevention and / or treatment of severe sepsis. The present invention has been completed. According to the present invention, a heteroaryl monocyclic pyrimidine derivative represented by the following formula (I) (hereinafter sometimes referred to as “the compound of the present invention”) is provided. That is, the present invention is as follows.

[Item 1] The following formula (I):

[Wherein, A ¹ and A ² represent the following formula (A) or (B),

When A ¹ is Formula ^(A), A ² represents formula (B),
When A ¹ is Formula (B), ^{A 2} represents formula (A),
X ^{^{^{^{is, -X 1 -, - X 1}}}} -NR 5 CO-X 2 -, - X 1 -CONR 5 -X 2 -, - X 1 -CO-X 2 -, - X 1 -NR 6 CONR 5 - X ^2- , -X ¹ -NR ⁵ -X ² -or -X ¹ -O-X ^2-
X ¹ represents an optionally substituted C _1-8 alkylene, and when X is —X ¹ —, X ¹ is an unsubstituted C _2-3 alkylene or an optionally substituted C _{4 -8} alkylene, and X is -X ¹ -NR ⁵ CO-X ^2- , -X ¹ -NR ⁶ CONR ⁵ -X ^2- , -X ¹ -NR ⁵ -X ² -or -X ¹ -O- When X ² —, X ¹ is an _optionally substituted C _2-8 alkylene;
X ² represents an _optionally substituted C _1-8 alkylene, wherein X represents —X ¹ —CONR ⁵ —X ² —, —X ¹ —NR ⁶ CONR ⁵ —X ² —, —X ^{When 1} —NR ⁵ —X ² — or —X ¹ —O—X ² —, X ² is an optionally substituted C _2-8 alkylene;
Y represents a hydrogen atom, an optionally substituted C _1-10 alkyl or an optionally substituted C _3-8 cycloalkyl,
Het represents a 5-6 membered heteroarylene,
W represents —W ¹ —, —NR ⁷ —W ¹ —, —NR ⁷ CO—W ¹ —, —CONR ⁷ —W ¹ —, or —O—W ¹ —, on the Het ring When the nitrogen atom and W are bonded, W represents —W ¹ — or —CONR ⁷ —W ¹ —
W ¹ represents an optionally substituted C _1-8 alkylene, and when W is —NR ⁷ —W ¹ —, —CONR ⁷ —W ¹ — or —O—W ¹ —, W ¹ is _Optionally substituted C _2-8 alkylene,
Z ¹ and Z ² are each independently a hydrogen atom; an optionally substituted C _1-10 alkyl; an optionally substituted C _3-8 cycloalkyl; a cyano; an optionally substituted C _{1 Represents -5} alkoxycarbonyl-; optionally substituted heteroaryl; halogen; optionally substituted C _1-5 alkoxy; or —NR ⁸ R ⁹ ,
Z ³ and Z ⁴ each independently represent a hydrogen atom; an optionally substituted C _1-10 alkyl; a halogen; or an optionally substituted C _1-5 alkoxy, or Z ³ and Z ⁴ May form a 5- to 8-membered saturated or unsaturated heterocyclic ring or saturated or unsaturated carbocyclic ring which may be substituted together when they are adjacent to each other,
R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, an optionally substituted C _1-10 alkyl, an optionally substituted C _3-8 cycloalkyl or a substituted Represents a 4-10 membered saturated heterocycle,
R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ each independently represents a hydrogen atom or an optionally substituted C _1-10 alkyl;
R ¹ -R ² , X ¹ -Y, R ¹ -R ⁵ , R ⁵ -X ² , R ¹ -X ¹ , R ¹ -X ² , R ³ -R ⁴ , R ³ -R ⁷ , R ^3- Each group of W ¹ or R ⁷ -W ^{1 is} a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atom of each group (the substituent of the ring is a ring (The number of nitrogen-containing saturated heterocycles formed is the same as that in formula (A) and formula (B), respectively). Independently, 0 to 2), wherein X is —X ¹ —, and the carbon atoms of each group of the group of R ¹ —X ¹ may be bonded to each other to be substituted; when forming a nitrogen-containing saturated heterocycle 10-membered, ^{X 1} is optionally _{C 4-8} alkylene optionally substituted, or, ^{X 1} is n- propylene (However, the position of forming the rings are carbon atoms at position 1 or 3 of the n- propylene) is'
Or a pharmaceutically acceptable salt thereof.

[Section 2] The alkyl part of each group of optionally substituted alkyl, optionally substituted alkoxy and optionally substituted alkoxycarbonyl-
(1) a halogen atom,
(2) hydroxyl group,
(3) Cyano,
(4) carboxyl,
(5) optionally substituted C _3-8 cycloalkyl,
(6) aryl which may be substituted,
(7) optionally substituted heteroaryl,
_{(8) C 1-5} alkoxy or fluorine may be substituted with atoms _{C 1-5} alkoxy,
(9) optionally substituted C _3-8 cycloalkoxy,
(10) C _1-5 alkoxycarbonyl-,
(11) -NR ¹⁰ R ¹¹ ,
(12) -CONR ¹⁰ R ¹¹ ,
(13) an optionally substituted 4- to 10-membered saturated heterocyclic ring, and (14) an optionally substituted C _1-5 alkylcarbonyl-
May be substituted with the same or different 1 to 5 substituents selected from the group consisting of
The optionally substituted alkylene is selected from the group consisting of the above (1) to (14), and (15) C _1-10 alkyl optionally substituted with 1 to 5 fluorine atoms or hydroxyl groups. It may be substituted with 1 to 5 substituents which are the same or different (wherein the groups shown in the above (6) and (7) are
(A) a hydroxyl group,
(B) halogen,
(C) C _1-10 alkyl optionally substituted with 1 to 5 fluorine atoms or hydroxyl groups,
(D) C _1-5 alkoxy optionally substituted with 1 to 5 fluorine atoms or hydroxyl groups,
(E) cyano,
(F) carboxyl,
(G) -NR ¹⁰ R ¹¹ ,
(H) -CONR ¹⁰ R ¹¹ ,
(I) means a group optionally substituted by 1 to 5 substituents selected from the group consisting of C _1-5 alkoxycarbonyl-, and (j) C _1-5 alkylcarbonyl-. ,
The groups shown in (5), (9), (13) and (14) are the above (a) hydroxyl group,
(B) halogen,
(C) C _1-10 alkyl optionally substituted with 1 to 5 fluorine atoms or hydroxyl groups,
(D) C _1-5 alkoxy optionally substituted with 1 to 5 fluorine atoms or hydroxyl groups,
(H) -CONR ¹⁰ R ¹¹ ,
(I) means a group optionally substituted by 1 to 5 substituents selected from the group consisting of C _1-5 alkoxycarbonyl-, and (j) C _1-5 alkylcarbonyl- );
The optionally substituted cycloalkyl (saturated carbocycle) and the optionally substituted saturated heterocycle are the above (a), (b), (c), (d), (h), (i) and A group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of (j);
The optionally substituted aryl (unsaturated carbocycle) and the optionally substituted heteroaryl (unsaturated heterocycle) are the same or different ones selected from the group consisting of the above (a) to (j); A group optionally substituted by 5 substituents;
R ¹⁰ and R ¹¹ are each independently a hydrogen atom or C _1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, or R ¹⁰ and R ¹¹ are taken together. A 4- to 10-membered nitrogen-containing saturated heterocyclic ring may be formed,
Item 12. The compound according to Item 1 or a pharmaceutically acceptable salt thereof.

[Claim 3] When A ¹ is formula (A), A ² is formula (B),
When A ¹ is formula (B), A ² is formula (A),
X ^{^{^{^{is, -X 1 -, - X 1}}}} -NR 5 CO-X 2 -, - X 1 -CONR 5 -X 2 -, - X 1 -CO-X 2 -, - X 1 -NR 6 CONR 5 - X ² —, —X ¹ —NR ⁵ —X ² — or —X ¹ —O—X ² —,
X ¹ is C _1-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-10 alkyl, wherein X 1 When is —X ¹ —, X ¹ is unsubstituted C _2-3 alkylene, or substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-10 alkyl. C _4-8 alkylene, and X is —X ¹ —NR ⁵ CO—X ² —, —X ¹ —NR ⁶ CONR ⁵ —X ² —, —X ¹ —NR ⁵ —X ² —. Or, in the case of —X ¹ —O—X ² —, X ¹ may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-10 alkyl. C _2-8 alkylene der ,
X ² is C _2-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-10 alkyl;
Y is a hydrogen atom; a C _1-10 alkyl optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-3 alkoxy; or a hydroxyl group, fluorine C _3-8 cycloalkyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of an atom and C _1-3 alkoxy;
Het is a 5-6 membered heteroarylene containing a nitrogen atom,
W is —W ¹ —, —NR ⁷ —W ¹ —, —NR ⁷ CO—W ¹ —, —CONR ⁷ —W ¹ — or —O—W ¹ —,
Here, when W is bonded to a nitrogen atom on the Het ring, W is —W ¹ — or —CONR ⁷ —W ¹ —,
W ¹ is C _1-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-10 alkyl, wherein W 1 Is —NR ⁷ —W ¹ —, —CONR ⁷ —W ¹ —, or —O—W ¹ —, W ¹ is the same or different from 1 to 5 selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-10 alkyl C _2-8 alkylene _optionally substituted with 3 substituents,
Z ¹ and Z ² are each independently a hydrogen atom; a hydroxyl group, a fluorine atom, a C _1-5 alkoxy (the group is the same or different from 1 to 5 selected from the group consisting of C _1-5 alkoxy and a fluorine atom) 3 may be substituted with a substituent) and 4-10 membered nitrogen-containing saturated same or different 1 to 3 of which may be substituted with a substituent C ₁ is selected from the group consisting of heterocyclic _-10 alkyl; C _3-8 cycloalkyl optionally substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-5 alkoxy; cyano; 1-3 number of is C _1-5 optionally alkoxycarbonyl-substituted by fluorine atom -; halogen and C _1-10 alkyl (the group may also be substituted with one to three fluorine atoms) consisting of Heteroaryl optionally substituted with the same or different 1 to 3 substituents selected from: halogen; substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom C _1-5 alkoxy; or —NR ⁸ R ⁹ ,
Each of Z ³ and Z ⁴ independently represents a hydrogen atom; a C _1-10 alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom; halogen Or C _1-5 alkoxy optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom, or when Z ³ and Z ⁴ are adjacent to each other 5- to 8-membered saturated or unsaturated heterocyclic ring or saturated or unsaturated carbocyclic ring which may be substituted together (substituent of the ring may be substituted in each group constituting the ring) The same as a good substituent)
R ¹ , R ² , R ³ and R ⁴ are each independently the same or selected from the group consisting of a hydrogen atom; a hydroxyl group, a fluorine atom, C _1-5 alkoxy, C _1-5 alkylcarbonyl- and carbamoyl C _1-10 alkyl optionally substituted with 1 to 3 different substituents; C optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group and a fluorine atom _3-8 cycloalkyl; or 1-3 identical or different substituents selected from the group consisting of hydroxyl, fluorine, C _1-10 alkyl, C _1-5 alkoxycarbonyl- and C _1-5 alkylcarbonyl- A 4- to 10-membered saturated heterocyclic ring optionally substituted by
R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, or the same or different 1 to 3 substituents selected from the group consisting of fluorine, hydroxyl group and C _1-5 alkoxy A C _1-10 alkyl _optionally substituted with
R ¹ -R ² , X ¹ -Y, R ¹ -R ⁵ , R ⁵ -X ² , R ¹ -X ¹ , R ¹ -X ² , R ³ -R ⁴ , R ³ -R ⁷ , R ^3- Each group of W ¹ or R ⁷ -W ^{1 is} a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atom of each group (the substituent of the ring is a ring; (The number of nitrogen-containing saturated heterocycles formed is the same as that in formula (A) and formula (B), respectively). Independently, 0 to 2), wherein X is —X ¹ —, and the carbon atoms of each group of the group of R ¹ —X ¹ may be bonded to each other to be substituted; When forming a 10-membered nitrogen-containing saturated heterocyclic ring, X ¹ is the same as selected from the group consisting of a hydroxyl group, a fluorine atom, and C _1-10 alkyl. C _4-8 alkylene which may be substituted with one or three different substituents, or n-propylene (provided that the ring is formed at the 1- or 3-position carbon atom of n-propylene). And when the carbon atom of each group of the X ¹ -Y group is bonded to form an optionally substituted 4- to 10-membered nitrogen-containing saturated heterocyclic ring, the nitrogen-containing saturated heterocyclic ring Is not morpholine,
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

[Item 4] A ¹ is the formula (A), and A ² is the formula (B).
Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.

[Item 5] Z ¹ and Z ² are each independently a hydrogen atom; a hydroxyl group, a fluorine atom, a C _1-5 alkoxy (the group is the same selected from the group consisting of C _1-5 alkoxy and a fluorine atom) Or optionally substituted with 1 to 3 different substituents) and substituted with 1 to 3 identical or different substituents selected from the group consisting of 4 to 10-membered nitrogen-containing saturated heterocycle C _1-10 alkyl; a C _3-8 cycloalkyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-5 alkoxy ,
Item 5. The compound according to any one of Items 1 to 4, or a pharmaceutically acceptable salt thereof.

[Item 6] R ¹ , R ² , R ³ and R ⁴ are each independently selected from the group consisting of a hydrogen atom; a hydroxyl group, a fluorine atom, C _1-3 alkoxy, C _1-5 alkylcarbonyl- and carbamoyl. C _1-10 alkyl optionally substituted with the same or different 1 to 3 substituents selected from the above, substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom Optionally substituted C _3-8 cycloalkyl; or 4 to 10 membered optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of hydroxyl, fluorine and C _1-10 alkyl A saturated heterocyclic ring,
Each group of R ¹ -R ² or R ³ -R ^{4 is} a 4- to 7-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atom of each group (the substituent of the ring is , Which may be the same as the substituent which may be substituted in each group constituting the ring),
Item 6. The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof.

[Item 7] Het is a divalent group of pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, triazole, thiazole, oxazole, isoxazole or isothiazole.
Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof.

[Item 8] Y is a hydrogen atom; or C _1-10 alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom, and X ¹ — Y is a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted containing carbon atoms of each group and containing exactly one nitrogen atom (the substituent on the ring is each group constituting the ring) And may be the same as the substituent which may be substituted, and may not form a morpholine ring as the ring),
Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.

[Item 9] W is -W ^1- , -NR ⁷ -W ¹ -or -O-W ^1- , and any ^one of R ³ -R ⁷ , R ³ -W ¹ or R ⁷ -W 1 The group is a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of carbon atoms of each group (the substituent of the ring may be substituted in each group constituting the ring) The same as a good substituent),
Item 9. The compound according to any one of Items 1 to 8, or a pharmaceutically acceptable salt thereof.

[Claim 10] X ^{^{^{is, -X 1 -, - X 1}}} -NR 5 CO-X 2 -, - X 1 -CONR 5 -X 2 - or ^-X 1 ^{-O-X 2} - is and, ^{X 1} - Any one of Y, R ¹ -X ¹ , R ¹ -X ² , R ¹ -R ⁵ or R ⁵ -X ² may be substituted by bonding of the carbon atoms of the respective groups 4 A 10-membered nitrogen-containing saturated heterocyclic ring (substituent of the ring is the same as the substituent which may be substituted in each group constituting the ring),
Item 10. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.

[Item 11] X ¹ is C _1-4 alkylene, and X ² is C _2-4 alkylene.
Item 11. The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof.

[Claim 12] X ¹ is n-propylene, wherein R ¹ -X ¹ does not form a ring,
The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

[Item 13] Z ³ and Z ⁴ are each independently a hydrogen atom; C _1-10 alkyl optionally substituted with fluorine; halogen; or C _1-5 alkoxy optionally substituted with fluorine is there,
Item 13. The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.

[Item 14] Het is a divalent group of pyridine or thiazole.
Item 14. The compound according to any one of Items 1 to 13, or a pharmaceutically acceptable salt thereof.

[Item 15] Het is a divalent group of pyrrole.
Item 14. The compound according to any one of Items 1 to 13, or a pharmaceutically acceptable salt thereof.

[Item 16] The compound according to item 1 or a pharmaceutically acceptable salt thereof selected from the following compounds:
5,6-Dimethyl-2- (2- (piperazin-1-yl) thiazol-5-yl) -N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine (Example 1),
5,6-Dimethyl-2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine (Examples) 2),
N1- (5-methoxy-2- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) pyrimidin-4-yl) -N3, N3-dimethylpropane-1,3-diamine (Examples) 4),
N1- (5,6-dimethyl-2- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) pyrimidin-4-yl) -N3, N3-dimethylpropane-1,3-diamine ( Example 5),
N1- (4,5-dimethyl-6- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) pyrimidin-2-yl) -N3, N3-dimethylpropane-1,3-diamine ( Example 6),
5,6-Dimethyl-2- (2- (4-methylpiperazin-1-yl) thiazol-5-yl) -N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine (Examples) 7),
5,6-Dimethyl-2- (2- (1-methylpiperidin-4-yl) thiazol-4-yl) -N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine (Examples) 9),
5,6-Dimethyl-2- (2- (4-methylpiperazin-1-yl) thiazol-4-yl) -N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine (Examples) 10), and 5,6-dimethyl-2- (1- (1-methylpiperidin-4-yl) -1H-indol-3-yl) -N- (3- (pyrrolidin-1-yl) propyl) pyrimidine -4-Amine (Example 11).

[Item 17] A pharmaceutical composition comprising the compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof.

[Item 18] A therapeutic and / or prophylactic agent for a disease associated with a toll-like receptor comprising the compound according to any one of items 1 to 16 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Item 19] A therapeutic agent for a disease associated with Toll-like receptor 7 and / or 9 comprising the compound according to any one of Items 1 to 16 or a pharmaceutically acceptable salt thereof as an active ingredient, and / or Or prophylactic agent.

[Item 20] The therapeutic and / or prophylactic agent according to item 18, wherein the disease associated with a toll-like receptor is sepsis, autoimmune disease or neurodegenerative disease.

[Item 21] The therapeutic and / or prophylactic agent according to item 19, wherein the disease associated with toll-like receptor 7 and / or 9 is sepsis, autoimmune disease or neurodegenerative disease.

[Item 22] A Toll-like receptor comprising administering a therapeutically effective amount of a compound according to any one of Items 1 to 16 or a pharmaceutically acceptable salt thereof to a mammal in need of treatment. A method for the treatment and / or prevention of diseases associated with the body.
[Item 23] Use of the compound according to any one of Items 1 to 16 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or preventive agent for a disease associated with a toll-like receptor. use.
[Item 24] The compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 16, for use in the treatment and / or prevention of a disease associated with a toll-like receptor.

The compounds of the present invention prevent and / or treat autoimmune diseases, specifically diseases involving autoimmunity (inflammation, allergy, asthma, graft rejection, graft-versus-host disease, infection, cancer), immunodeficiency It is useful as a prophylactic and / or therapeutic agent for symptom or neurodegenerative disease (Alzheimer, Parkinson's disease, etc.). In addition, by finding a TLR inhibitor that selectively inhibits TLR, it is useful as a pharmaceutical effective for the prevention and / or treatment of sepsis, particularly severe sepsis. In addition, by finding a TLR inhibitor that selectively inhibits TLR, a cancer growth suppressing effect and / or a cancer cell death inducing effect can be expected, and it is also useful as a pharmaceutical effective for the prevention and / or treatment of cancer. It is.

Hereinafter, the present invention will be described in more detail.
In the following description, the compound represented by formula (I) is referred to as compound (I). The same applies to the compounds of other formula numbers.

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

In addition, the compounds of formula (I) may have one or more than one asymmetric carbon atom, and may cause geometric isomerism and axial chirality. May exist. In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention.
In addition, a deuterium converter obtained by converting any one or two or more ¹ H of compound (I) to ² H (D) is also encompassed in compound (I) of the present invention.

In the present specification, the number of substituents in the “substituted” group is not particularly limited as long as it can be substituted, unless otherwise specified, and is 1 or 2 or more. In the description in the present specification, a group not particularly described means an unsubstituted group. In addition, unless otherwise specified, the description of each group also applies when the group is a part of another group or a substituent.

(I) “Alkyl” means a linear or branched saturated hydrocarbon group. For example, “C _1-3 alkyl” or “C _1-10 alkyl” has 1 carbon atom. Each represents ˜3 or 1-10 alkyl. Specifically, in the case of “C _1-3 alkyl”, methyl, ethyl, propyl, isopropyl, etc., and in the case of “C _1-10 alkyl”, in addition to the above, butyl, isobutyl, sec -Butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, isooctyl, nonyl, decyl and the like. Among these, “C _1-3 alkyl” is preferable.
(Ii) “Cycloalkyl” or “saturated carbocycle” means a cyclic saturated hydrocarbon group, for example, “C _3-8 cycloalkyl” means a 3- to 8-membered cyclic saturated hydrocarbon group. means. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferably, a 5- to 7-membered cycloalkyl group is used.

(Iii) “Aryl” or “unsaturated carbocycle” includes 6-12 membered monocyclic, bicyclic aryl groups. Specific examples include phenyl, naphthyl, indenyl and the like. Preferable examples include monocyclic or 8 to 10-membered bicyclic aryl groups having 6 carbon atoms, such as phenyl and naphthyl.
(Iv) “Heteroaryl” or “unsaturated heterocycle” is a 5- to 7-membered single ring containing 1 to 4 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Examples thereof include a cyclic aromatic heterocycle, a 9 to 11-membered bicyclic aromatic heterocycle, and a 12 to 15-membered tricyclic aromatic heterocycle. Specifically, pyridyl, pyrazinyl, pyrimidinyl, benzimidazolyl, 2-oxobenzoxazolyl, benzotriazolyl, benzofuryl, benzothienyl, purinyl, benzoxazolyl, benzothiazolyl, imidazolyl, indolyl, isoquinolyl, pyrrolinyl, quinazolinyl, Cinnolinyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isothiazolyl, thienyl, furyl and the like. Preferable examples include 5-membered or 6-membered monocyclic aromatic heterocycles, and specific examples include pyridyl, imidazolyl, pyrazolyl, thiazolyl and tetrazolyl.

(V) “Halogen” means each atom of fluorine, chlorine, bromine or iodine. Preferably, each atom of fluorine, chlorine or bromine is used.
(Vi) “Alkoxy” means a group in which a linear or branched saturated hydrocarbon group is bonded via an oxygen atom, for example, “C _1-3 alkoxy” or “C ₁ the _-5 alkoxy "means an alkoxy of 1 to 3 or 1 to 5 carbon atoms. Specifically, in the case of “C _1-3 alkoxy”, methoxy, ethoxy, propoxy, isopropoxy and the like can be mentioned, and in the case of “C _1-5 alkoxy”, butoxy, isobutoxy, and sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, tert-pentoxy and the like. Among these, “C _1-3 alkoxy” is preferable.

(Vii) “saturated heterocycle” means a carbon atom and a saturated ring containing 1 to 3 heteroatoms in addition to carbon atoms; for example, “4 to 10-membered saturated heterocycle” means other than carbon atoms Means a saturated ring composed of 4 to 10 atoms including 1 to 3 heteroatoms. Here, examples of the hetero atom include the same or different nitrogen atom, oxygen atom or sulfur atom, preferably nitrogen atom or oxygen atom, more preferably nitrogen atom. Specific examples include azetidinyl, pyrrolidyl, piperidyl, morpholinyl, homopiperidyl, piperazinyl, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxotetrahydrothiopyranyl, dioxotetrahydrothiopyranyl and the like. It is done. Preferred is a 4- to 7-membered saturated heterocyclic ring, and specific examples include azetidinyl, pyrrolidyl, piperidyl, morpholinyl, homopiperidyl, piperazinyl, tetrahydrofuranyl and tetrahydropyranyl. “4- to 10-membered nitrogen-containing saturated heterocyclic ring” means a saturated ring composed of 4 to 10 atoms containing 1 to 2 nitrogen atoms in addition to carbon atoms (wherein the saturated ring is further 1 Carbon atoms may be substituted with oxygen or sulfur atoms). A 4- to 7-membered nitrogen-containing saturated heterocyclic ring is preferable.
(Viii) “Alkylene” means a straight hydrocarbon chain, unless otherwise defined, in which part of the methylene may be substituted with cycloalkylene. For example, “C _2-4 alkylene”, “C _2-8 alkylene” or “C _1-8 alkylene” means a straight hydrocarbon chain having 2 to 4, 2 to 8 or 1 to 8 carbon atoms. Means. Specifically, in the case of “C _2-4 alkylene”, ethylene, propylene, butylene, cyclobutylene and the like can be mentioned. In the case of “C _2-6 alkylene”, in addition to the above, pentamethylene In the case of “C _1-8 alkylene”, in addition to the above, methylene, octamethylene and the like can be mentioned. Among these, “C _2-4 alkylene” is preferable. Moreover, when the said alkylene substitutes an alkyl, two same or different alkyl couple | bonded with the same carbon atom may form a ring together.
(Iv) Specific examples of “C _1-5 alkylcarbonyl-” include methylcarbonyl-, ethylcarbonyl-, propylcarbonyl-, isopropylcarbonyl-, butylcarbonyl-, isobutylcarbonyl-, tert-butylcarbonyl- and the like. It is done. “C _1-3 alkylcarbonyl-” is preferable, and methylcarbonyl- is more preferable. Similarly, specific examples of “C _1-5 alkoxycarbonyl-” include methoxycarbonyl-, ethoxycarbonyl-, propoxycarbonyl-, isopropoxycarbonyl-, butoxycarbonyl-, isobutoxycarbonyl-, tert-butoxycarbonyl-, pen And the like. “C _1-3 alkoxycarbonyl-” is preferable, and methoxycarbonyl- is more preferable.

As the substituent of the alkyl part of each group of “optionally substituted alkyl”, “optionally substituted alkoxy” and “optionally substituted alkoxycarbonyl-”,
(1) a halogen atom,
(2) hydroxyl group,
(3) Cyano,
(4) carboxyl,
(5) optionally substituted C _3-8 cycloalkyl,
(6) aryl which may be substituted,
(7) optionally substituted heteroaryl,
_{(8) C 1-5} alkoxy or fluorine may be substituted with atoms _{C 1-5} alkoxy,
(9) optionally substituted C _3-8 cycloalkoxy,
(10) C _1-5 alkoxycarbonyl-,
(11) -NR ¹⁰ R ¹¹ ,
(12) -CONR ¹⁰ R ¹¹ ,
(13) an optionally substituted 4- to 10-membered saturated heterocyclic ring, and (14) an optionally substituted C _1-5 alkylcarbonyl-
(R ¹⁰ and R ¹¹ are as defined above),
Examples of the optionally substituted alkylene substituent include (1) to (14) and (15) C _1-10 alkyl optionally substituted with 1 to 5 fluorine atoms or hydroxyl groups. (Wherein the groups shown in the above (6) and (7) are
(A) a hydroxyl group,
(B) halogen,
(C) C _1-10 alkyl optionally substituted with 1 to 5 fluorine atoms or hydroxyl groups,
(D) C _1-5 alkoxy optionally substituted with 1 to 5 fluorine atoms or hydroxyl groups,
(E) cyano,
(F) carboxyl,
(G) —NR ¹⁰ R ¹¹
(H) -CONR ¹⁰ R ¹¹ ,
(I) means a group optionally substituted by 1 to 5 substituents selected from the group consisting of C _1-5 alkoxycarbonyl-, and (j) C _1-5 alkylcarbonyl-. ,
The groups shown in (5), (9), (13) and (14) are the above (a) hydroxyl group,
(B) halogen,
(C) C _1-10 alkyl optionally substituted with 1 to 5 fluorine atoms or hydroxyl groups,
(D) C _1-5 alkoxy optionally substituted with 1 to 5 fluorine atoms or hydroxyl groups,
(H) -CONR ¹⁰ R ¹¹ ,
(I) means a group optionally substituted by 1 to 5 substituents selected from the group consisting of C _1-5 alkoxycarbonyl-, and (j) C _1-5 alkylcarbonyl- ). Among these, a substituent of (1), (2), (8), (11), (12) or (13) is preferable, and a fluorine atom, (2) or unsubstituted (8) is more preferable. Is mentioned.

Examples of the substituent of the optionally substituted cycloalkyl (saturated carbocyclic ring) and optionally substituted saturated heterocyclic ring include the aforementioned (a), (b), (c), (d), (h), (I) and (j) are mentioned. Among these, a substituent of (a), (b), (c) or (h) is preferable, and (a), a fluorine atom or (c) is more preferable.

Examples of the substituent of the optionally substituted aryl (unsaturated carbocycle) and the optionally substituted heteroaryl (unsaturated heterocycle) include the above (a) to (j). Among these, a substituent of (a), (b), (c) or (h) is preferable, and (a), a fluorine atom or (c) is more preferable.

Examples of the pharmaceutically acceptable salt of compound (I) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, benzenesulfonate, benzoate, citric acid, and the like. Acid addition salts such as acid salts, fumarate salts, gluconate salts, lactate salts, maleate salts, malate salts, oxalate salts, methanesulfonate salts, tartrate salts, sodium salts, potassium salts, etc. Alkali metal salts such as alkali metal salts, magnesium salts and calcium salts, metal salts such as aluminum salts and zinc salts, ammonium salts such as ammonium and tetramethylammonium, organic amine additions such as morpholine addition salts and piperidine addition salts And amino acid addition salts such as glycine addition salts, phenylalanine addition salts, lysine addition salts, aspartic acid addition salts, glutamic acid addition salts, and the like.

Among the compounds of the present invention represented by formula (I), A ¹ , A ² , X, X ¹ , X ² , Y, W, W ¹ , Z ¹ to Z ⁴ , R ¹ to R ¹¹ , and Het Of these groups, preferred groups are as follows, but the present invention is not limited to the compounds listed below. Moreover, the preferable substituent quoted by each group is a preferable group of each group alone, and preferable rings when forming a ring with other groups are as described below. In addition, “-” representing the left and right bond chains of the substituents such as X and W represents that they are bonded to the left and right groups as shown in the chemical formula.

Preference is given to compounds of the formula (I) in which A ¹ is the formula (A) and A ² is the formula (B).
The ^{^{^{X, -X 1 -, - X}}} 1 -NR 5 CO-X 2 -, - X 1 -CONR 5 -X 2 - or ^-X 1 ^{-O-X 2} -, more preferably, -X ¹ — or —X ¹ —O—X ² —.
X ¹ is preferably C _1-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-10 alkyl, and more preferably , C _1-4 alkylene.
X ² is preferably C _2-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-10 alkyl, and more preferably , C _2-6 alkylene, more preferably C _2-4 alkylene.

Y represents a hydrogen atom; a C _1-10 alkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-3 alkoxy; or a hydroxyl group; C _3-8 cycloalkyl optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of a fluorine atom and C _1-3 alkoxy is preferable, more preferably a hydrogen atom; or a hydroxyl group And C _1-10 alkyl optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of fluorine atoms, more preferably a hydrogen atom or C _1-4 alkyl.

Het is a 5- to 6-membered monocyclic nitrogen-containing heterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and containing at least one nitrogen atom. Arylene is meant, and is preferably a 5- to 6-membered monocyclic nitrogen-containing heteroarylene containing only one nitrogen atom. The point where the heteroarylene is bonded to the pyrimidine ring is a carbon atom constituting the heteroarylene. In addition, the portion where the heteroarylene is bonded to W may be any of a carbon atom and a nitrogen atom constituting the heteroarylene as long as bonding is possible. Specific Het is preferably a divalent group of pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, triazole, thiazole, oxazole, isoxazole or isothiazole, more preferably pyridine, pyrimidine, pyridazine, thiazole. , Oxazole and pyrrole, more preferably a pyridine or thiazole divalent group.
Z ³ and Z ⁴ bonded to Het may be bonded to any of the carbon atom and hetero atom constituting the heteroarylene as long as bonding is possible.

The ^{^{W, -W 1 -, - NR}} 7 -W 1 - or ^{-O-W 1} -, more preferably, ^-NR 7 -W ¹ - or ^{-O-W 1} - a, and still more preferably -NR ⁷ -W ^1- .
As W ^1, preferably hydroxyl, include fluorine atom and C _1-10 identical or different one to three good C _1-8 alkylene optionally substituted with a substituent selected from the group consisting of alkyl, more Preferably, C _2-4 alkylene is used.

Z ¹ and Z ² are preferably a hydrogen atom; a hydroxyl group, a fluorine atom, a C _1-5 alkoxy (the group is the same or different 1 to 3 selected from the group consisting of C _1-5 alkoxy and a fluorine atom) C _1-10 alkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of 4-10 membered nitrogen-containing saturated heterocycle C _3-8 cycloalkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-5 alkoxy; cyano; 1 to 3 fluorines optionally substituted C _1-5 also be alkoxycarbonyl with atoms -; halogen and C _1-10 alkyl (in which from 1 to 3 fluorine atoms may be substituted with) or the group consisting of Heteroaryl optionally substituted with the same or different 1 to 3 substituents selected; halogen; substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom C _1-5 alkoxy; or —NR ⁸ R ⁹ may be mentioned. More preferably, a hydrogen atom; a hydroxyl group, a fluorine atom, a C _1-5 alkoxy (the group is substituted with the same or different 1 to 3 substituents selected from the group consisting of C _1-5 alkoxy and a fluorine atom) And a C _1-10 alkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of 4 to 10-membered nitrogen-containing saturated heterocycles; hydroxyl group, fluorine atom And C _3-8 cycloalkyl optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of C _1-5 alkoxy, and more preferably a hydrogen atom; a hydroxyl group, C _{1 -5} alkoxy and 4 the same is selected from the group consisting of nitrogen-containing saturated heterocyclic ring-6-membered or different one to three optionally substituted with a substituent C _1-5 alkyl; or C _-8 cycloalkyl.

Z ³ and Z ⁴ are preferably a hydrogen atom; a C _1-10 alkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom; a halogen; or a hydroxyl group And C _1-5 alkoxy which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of fluorine atoms, and more preferably, a hydrogen atom; Good C _1-10 alkyl; halogen; or C _1-5 alkoxy optionally substituted with fluorine, more preferably a hydrogen atom, halogen or C _1-5 alkoxy.

R ¹ , R ² , R ³ and R ⁴ are preferably substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydrogen atom; a hydroxyl group, a fluorine atom, C _1-5 alkoxy and carbamoyl. An optionally substituted C _1-10 alkyl; a C _3-8 cycloalkyl optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom; or a hydroxyl group, a fluorine atom _{4- to 10-} membered optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of C _1-10 alkyl, C _1-5 alkoxycarbonyl- and C _1-5 alkylcarbonyl- Of the saturated heterocyclic ring. More preferably, a hydrogen atom; a C _1-10 alkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom, C _1-3 alkoxy and carbamoyl; a hydroxyl group And a C _3-8 cycloalkyl optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of fluorine atoms; or selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-10 alkyl And 4- to 10-membered saturated heterocyclic ring which may be substituted with the same or different 1 to 3 substituents. More preferably, a hydrogen atom; or a C _1-10 alkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-3 alkoxy may be mentioned. . Most preferably, it is a hydrogen atom or C _1-10 alkyl.

R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are preferably substituted with the same or different 1 to 3 substituents selected from the group consisting of hydrogen atom, fluorine, hydroxyl group and C _1-5 alkoxy. C _1-10 alkyl which may be optionally _substituted is mentioned, more preferably, a hydrogen atom or C _1-10 alkyl is mentioned, and still more preferably, C _1-4 alkyl is mentioned.
R ¹⁰ and R ¹¹ are preferably a hydrogen atom; a C _1-10 alkyl optionally substituted with 1 to 5 fluorine atoms; or a 4 to 10 member formed by R ¹⁰ and R ^{11 taken} together A nitrogen-containing saturated heterocyclic ring, more preferably a hydrogen atom or C _1-10 alkyl, and still more preferably C _1-4 alkyl.

R ¹ -R ² , X ¹ -Y, R ¹ -R ⁵ , R ⁵ -X ² , R ¹ -X ¹ , R ¹ -X ² , R ³ -R ⁴ , R ³ -R ⁷ , R ^3- Each group of W ¹ or R ⁷ -W ^{1 is} a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atom of each group (the substituent of the ring is a ring The same as the substituent which may be substituted in each of the constituent groups). “The carbon atoms of each group are bonded to form a ring” means that, as shown below, each hydrogen atom bonded to each carbon atom is removed and each carbon atom is bonded. Means to form a ring. Specific rings are listed below, but are not limited to these exemplified rings. The number of nitrogen-containing saturated heterocycles formed is independently 0 to 2 in formula (A) and formula (B).

Preferred examples when each group of R ¹ -R ² or R ³ -R ⁴ forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atoms of the respective groups The following structures are mentioned as:

More preferred are r ¹ -a, r ¹ -b, r ¹ -c, r ¹ -d and r ¹ -f, and more preferred are r ¹ -b, r ¹ -c, r ¹ -d. And r ¹ -f.

When X ¹ -Y forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atoms of each group, preferred examples thereof include the following structures.

More preferably, ya, yc, yd, ye, yf, yg, and yh are mentioned, and more preferably ya, yc, ye. , Yf and yh.

When R ¹ -R ⁵ forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atoms of each group, preferred examples thereof include the following structures.

More preferable examples include r ⁵ -a, r ⁵ -b, r ⁵ -c, r ⁵ -d, and r ⁵ -e, and more preferably r ⁵ -a, r ⁵ -b, and r ^5. -E.

When R ⁵ -X ² forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atoms of each group, preferred examples thereof include the following structures.

More preferable examples include x ² -a, x ² -b, x ² -c, x ² -d, x ² -e, x ² -f, x ² -g, and x ² -j, and more preferable. Includes x ² -a, x ² -c, x ² -d, x ² -e, x ² -f, and x ² -j.

Preferred examples when each group of R ¹ -X ¹ and R ¹ -X ² forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atoms of the respective groups The following structures are mentioned as: Here, X is —X ¹ —, and the carbon atoms of each group of the group of R ¹ —X ¹ are bonded to form an optionally substituted 4- to 10-membered nitrogen-containing saturated heterocyclic ring. In some cases, X ¹ is optionally substituted C _4-8 alkylene, or n-propylene (where the ring-forming position is the 1- or 3-position carbon atom of n-propylene).

More preferably, x ¹ -a, x ¹ -b, x ¹ -c, x ¹ -d, x ¹ -e, x ¹ -f, x ¹ -g and x ¹ -k are mentioned, and more preferably , X ¹ -b, x ¹ -c, x ¹ -e and x ¹ -g.

When R ³ -R ⁷ forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atoms of each group, preferred examples thereof include the following structures.

More preferably, r ³ -a, r ³ -b, r ³ -c, r ³ -d, r ³ -e, and r ³ -g are mentioned, and more preferably, r ³ -a, r ^3- b, r ³ -c, and r ³ -g.

When R ³ -W ¹ forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atoms of each group, preferred examples thereof include the following structures.

More preferably, w ¹ -a, w ¹ -c, w ¹ -d, w ¹ -e, w ¹ -f, w ¹ -g, w ¹ -h, w ¹ -i, w ¹ -j, w ¹ -k and w ¹ -p are mentioned, and more preferred are w ¹ -a, w ¹ -c, w ¹ -e, w ¹ -f, w ¹ -h and w ¹ -j.

When R ⁷ -W ¹ forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atoms of each group, preferred examples thereof include the following structures.

More preferably, r ⁷ -a, r ⁷ -c, r ⁷ -d, r ⁷ -e, r ⁷ -f, r ⁷ -g, r ⁷ -h, r ⁷ -i, r ⁷ -j, r ^{^{^{^{7 -k, r 7 -l, r}}}} 7 -m, r 7 -n, r 7 -o, include ^r 7 -p and ^r 7 -w, more ^{^preferably,} r 7 ^-a, r 7 -c , R ⁷ -e, r ⁷ -g, r ⁷ -h, r ⁷ -j, r ⁷ -l and r ⁷ -o.

When Z ³ and Z ⁴ form a 5- to 8-membered saturated or unsaturated heterocycle or saturated or unsaturated carbocycle which may be substituted together when adjacent, Z ³ and The following groups represented by the heteroaryl ring to which Z ⁴ is bonded are preferred examples.

[Wherein, R ′ and R ″ each independently represent (c), (i), (j) or a hydrogen atom in Item 2, o represents an integer of 1 to 4, and p represents 0 to 5] Integer, q is an integer from 0 to 5, and the sum of the integers of p and q is 2 to 5.]

More preferably, z ³ -d, z ³ -e, z ³ -f, z ³ -j, z ³ -k, z ³ -l, z ³ -m, z ³ -n, z ³ -o, z ³ -q, z ³ -v, z ³ -w, z ³ -x, z ³ -y, z ³ -aa, and z ³ -bb, more preferably z ³ -d, z ^3- j, z ³ -m, z ³ -y, z ³ -aa, and z ³ -bb.

Note that the following abbreviations may be used to simplify the description in this specification. o-: ortho-, p-: para-, t-: tert-, s-: sec-, THF: tetrahydrofuran, DME: ethylene glycol dimethyl ether, DMF: N, N-dimethylformamide, DMA: N, N-dimethyl Acetamide, NMP: N-methylpyrrolidinone, DCE: 1,2-dichloroethane, DMSO: dimethyl sulfoxide, CDCl ₃ : deuterated chloroform, DMSO-d ₆ : deuterated dimethyl sulfoxide, OMs: methanesulfonyloxy, OTs: toluenesulfonyloxy, OTf : Trifluoromethanesulfonyloxy, s: singlelet, d: doublet, t: triplet, m: multiplet, Boc: t-butoxycarbonyl, DPPF: 1,1′-bis (diphenylphosphino) ferrocene, DPPE: 1,2-bis (diphenyl Phosphino) ethane, DPPP: 1,3-bis (diphenylphosphino) propane, DPPB: 1,4-bis (diphenylphosphino) butane, BINAP®: 2,2′-bis (diphenylphosphino)- 1,1′-binaphthyl, DPE-Phos®: bis (2-diphenylphosphinophenyl) ether, XANT-Phos®: 9,9-dimethyl-4,5-bis (diphenylphosphino) Xanthine, S-Phos: 2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl (registered trademark), X-Phos: 2-dicyclohexylphosphino-2 ′, 4 ′, 6′- Triisopropyl-1,1′-biphenyl (registered trademark), HATU: O- (7-azabenzotriazol-1-yl) -1,1,3,3 Tetramethyluronium hexafluorophosphate.

The production method of the compound (I) of the present invention is described below. Compounds (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) and (Ij) are compounds included in compound (I) It is. Compound (I) can be obtained by the method shown in the following production methods 1 to 12 or a method analogous thereto. The compound in the reaction formula includes a case where a salt is formed, and examples of the salt include those similar to the salt of compound (I).

Production method 1:
Among the compounds (I), A ¹ is the formula (A), A ² is the compound (Ia) of the formula (B), and A ¹ is the formula (B), and A ² is the formula (A) A certain compound (Ib) can be obtained by the production method shown below.

(Wherein R ¹ , R ² , R ³ , R ⁴ , W, X, Y, Z ¹ , Z ² , Z ³ , Z ⁴ and Het are as defined above. R ^a is substituted. And R ^b is a hydrogen atom or an optionally substituted alkyl group, and Hal ^a is a chlorine atom or a bromine atom.)

[Step 1]
Compound (III) is obtained by reacting Compound (II) with 1 to 20 equivalents, preferably 2 to 10 equivalents of urea in the presence of 2 to 10 equivalents, preferably 3 to 5 equivalents of a base in a solvent. be able to. Compound (II) is a commercially available product or a known method [for example, Journal of American Chemical Society, 316 (1920), Journal of American Chemical Society, 580 (1942), Journal of American Chemical Society, 831 (1952)] or It is synthesized by a method according to it.

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, DMA, NMP, methanol , Ethanol, 1-propanol, 2-propanol and the like can be used alone or in admixture thereof, with methanol or ethanol being preferred.
As the base, for example, various alkali or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like can be used, and among them, sodium methoxide or sodium ethoxide is preferable.
The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 100 ° C., usually for 1 to 60 hours.

[Step 2]
Compound (IV) can be obtained by reacting compound (III) obtained in step 1 with a halogenating agent in an excess amount, preferably 3 to 10 equivalents, in a solvent or without a solvent.

Examples of the halogenating agent include phosphorus oxychloride, phosphorus pentachloride, phosphorus oxybromide and the like. The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, DCE, THF, 1,4-dioxane, DME, chloroform, benzene, toluene, xylene, ethyl acetate , Triethylamine, pyridine, N, N-diisopropylethylamine, N, N-dimethylaniline, N, N-diethylaniline and the like can be used alone or as a mixture thereof.
The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent or halogenating agent, preferably 50 to 140 ° C., usually for 1 to 24 hours.

[Step 3]
Compound (IV) obtained in Step 2 is added in a solvent in the presence of 1 to 5 equivalents, preferably 1.5 to 2 equivalents of a base, and 1 to 5 equivalents, preferably 1.2 to 3 equivalents of compound (V ) To give compound (VI-a) and / or (VI-b).

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, DMA, NMP, methanol , Ethanol, 1-propanol, 2-propanol and the like can be used alone or in admixture thereof, and among these, 1,4-dioxane, NMP or 2-propanol is preferable.
Examples of the base include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium acetate, inorganic bases such as sodium hydroxide and potassium hydroxide, aromatic amines such as pyridine and lutidine, triethylamine and tripropylamine. Tertiary amines such as tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-diisopropylethylamine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, Alkali metal hydrides such as sodium hydride and potassium hydride, among them, potassium carbonate, triethylamine or N, N-diisopropylethylamine are preferred.
The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 180 ° C., usually for 0.5 to 24 hours.

[Step 4]
Compound (VI-a) or Compound (VI-b) obtained in Step 3 is used in a solvent in an amount of 1 to 10 equivalents, preferably 2 to 4 equivalents, and 0.01 to 1 equivalents, preferably 0.05. ~ 0.2 equivalents of palladium catalyst, optionally in the presence of 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of a phosphine ligand, 1 to 5 equivalents, preferably 1.1 to Compound (Ia) or compound (Ib) can be obtained by reacting with 2 equivalents of compound (VII).

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, water and the like are used alone. Alternatively, they can be used in combination, and among them, a mixed solvent of DMF and water, DME and water, or 1,4-dioxane and water is preferable.
Examples of the palladium catalyst include zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis A divalent catalyst such as (diphenylphosphinoferrocene) palladium dichloride can be used, among which tetrakistriphenylphosphine palladium or palladium acetate is preferred.
Examples of phosphine ligands include monodentate ligands such as o-tolylphosphine, S-Phos or X-Phos, DPPF, DPPE, DPPP, DPPB, BINAP, XANT-Phos or DPE-Phos. The following bidentate ligands can be used, and S-Phos or X-Phos is particularly preferable.
Examples of the base include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate or potassium phosphate, among which sodium carbonate, potassium carbonate or potassium phosphate is preferable. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at 50 to 180 ° C. or under microwave irradiation, usually for 0.5 to 24 hours.

Production method 2:
Among compounds (I), compound (Ic) in which A ¹ is formula (A), A ² is formula (B), and W is —NR ⁷ —W ¹ — is compound (VI-a) Thus, it can be obtained by the production method shown below.

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁷ , W ¹ , X, Y, Z ¹ , Z ² , Z ³ , Z ⁴ and Het are as defined above, and R ^b is A hydrogen atom or an optionally substituted alkyl group, Hal ^a and Hal ^b are each independently a chlorine atom or a bromine atom.)

[Step 5]
Compound (IX) can be obtained by reacting Compound (VI-a) obtained in Step 3 and Compound (VIII) in the same manner as in Step 4.

[Step 6]
Compound (IX) obtained in Step 5 is added in a solvent in an amount of 1 to 10 equivalents, preferably 3 to 5 equivalents of a base, and 0.01 to 1 equivalents, preferably 0.05 to 0.2 equivalents of a phosphine ligand. And 1 to 5 equivalents, preferably 1 to 2 equivalents of compound (X) in the presence of 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of palladium catalyst, Ic) can be obtained.

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, benzene, toluene, xylene and the like are used alone or in combination. Among them, toluene or 1,4-dioxane is preferable.
Examples of the phosphine ligand include tridentate phosphine such as triphenylphosphine, o-tolylphosphine, trifuranylphosphine, and tri-t-butylphosphine, or BINAP, 2,2′-bis (ditolylphosphino ) -1,1′-binaphthyl, DPE-Phos, XANT-Phos and other bidentate phosphines can be used, and among these, BINAP is preferable.
Examples of the palladium catalyst include zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis A divalent catalyst such as (diphenylphosphinoferrocene) palladium dichloride can be used, and tris (dibenzylideneacetone) dipalladium or palladium acetate is particularly preferable.
As the base, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium acetate, various alkalis such as sodium methoxide, sodium ethoxide and potassium t-butoxide, or alkaline earth metal alkoxides can be used. Of these, cesium carbonate or sodium t-butoxide is preferred. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably between 50 and 180 ° C., under heating or under microwave irradiation, usually for 0.5 to 24 hours. A compound in which A ¹ is the formula (B) and A ² is the formula (A) can also be obtained from the compound (VI-b) obtained in Step 3 by the same production method.

Production method 3:
Among the compounds (I), the compound (Id) in which A ¹ is the formula (A), A ² is the formula (B), and W is —O—W ¹ — is obtained from the compound (VI-a). It can be obtained by the production method shown below.

(Wherein R ¹ , R ² , R ³ , R ⁴ , W ¹ , X, Y, Z ¹ , Z ² , Z ³ , Z ⁴ and Het have the same meanings as described above. R ^b represents a hydrogen atom. Or an alkyl group which may be substituted, and Hal ^a is a chlorine atom or a bromine atom.)

[Step 7]
Compound (XII) can be obtained by reacting compound (VI-a) obtained in step 3 and compound (XI) in the same manner as in step 4.

[Step 8]
Compound (XII) obtained in Step 7 is added in a solvent in the presence of 1 to 10 equivalents, preferably 1 to 3 equivalents of phosphine, and 1 to 10 equivalents, preferably 1 to 3 equivalents of an azo compound or Kakuda reagent. Compound (Id) can be obtained by reacting with ˜5 equivalents, preferably 1 to 3 equivalents of the corresponding alcohol derivative. Alternatively, the compound (XII) obtained in Step 7 is used in a solvent in the presence or absence of 1 to 10 equivalents, preferably 1 to 3 equivalents of a base, and 1 to 5 equivalents, preferably 1 to 3 equivalents. Compound (Id) can also be obtained by reacting with an alkyl halogen derivative or the like.

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, dichloromethane, DCE, chloroform, benzene, toluene, xylene, DMF , DMA, NMP, methanol, ethanol, 1-propanol, 2-propanol and the like can be used alone or as a mixture thereof. Among them, THF, dichloromethane, toluene and DMF are preferable.
Examples of the phosphine to be used include triphenylphosphine, trimethylphosphine, tributylphosphine and the like, among which triphenylphosphine is preferable.
Examples of the azo compound include diethyl azodicarboxylate, diisopropyl azodicarboxylate, dicyclohexyl azodicarboxylate, dibenzyl azodicarboxylate, and the like, among which diethyl azodicarboxylate or diisopropyl azodicarboxylate is preferable.
Examples of the base include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium acetate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine and 4-dimethylaminopyridine. , Tertiary amines such as N, N-diisopropylethylamine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride Of these, potassium carbonate, cesium carbonate, pyridine, N, N-diisopropylethylamine or sodium hydride are preferred. The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably room temperature to 100 ° C., usually for 0.5 to 24 hours. A compound in which A ¹ is the formula (B) and A ² is the formula (A) can also be obtained from the compound (VI-b) obtained in Step 3 by the same production method.

Production method 4:
Among compounds (I), compound (Ia) in which A ¹ is formula (A) and A ² is formula (B) can also be obtained by the production method shown below.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , W, X, Y, Z ¹ , Z ² , Z ³ , Z ⁴ and Het are as defined above. R ^a is substituted. An alkyl group which may be substituted, and Hal ^a is a chlorine atom or a bromine atom.)

[Step 9]
By reacting 1 to 10 equivalents, preferably 1 to 3 equivalents of compound (XIII) with compound (II) in a solvent in the presence of 2 to 10 equivalents, preferably 2 to 4 equivalents of a base, XIV) can be obtained. Compound (XIII) is synthesized as a commercially available product or by a known method [for example, Chemical and Pharmaceutical Bulletin, 55, 372-375 (2007)] or a method analogous thereto.

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, DMA, NMP, methanol , Ethanol, 1-propanol, 2-propanol, and the like can be used alone or as a mixture thereof. Among these, methanol or ethanol is preferable.
As the base, for example, various alkali or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like can be used, and among them, sodium methoxide or sodium ethoxide is preferable. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 100 ° C., usually for 1 to 60 hours.

[Step 10]
Compound (XV) can be obtained by reacting compound (XIV) obtained in step 9 in the same manner as in step 2.

[Step 11]
Compound (Ia) can be obtained by reacting compound (XV) obtained in step 10 and compound (V) in the same manner as in step 3.

Production method 5:
Among the compounds (I), the compound (Ic) in which A ¹ is the formula (A), A ² is the formula (B), and W is —NR ⁷ —W ¹ — is, for example, from the compound (II) It can also be obtained by the following production method.

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁷ , W ¹ , X, Y, Z ¹ , Z ² , Z ³ , Z ⁴ and Het are as defined above, Hal ^a and Hal ^b is each independently a chlorine atom or a bromine atom, and R ^a is an optionally substituted alkyl group.)

[Step 12]
Compound (XVII) can be obtained by reacting Compound (XVI) and Compound (II) in the same manner as in Step 9. Compound (XVI) is synthesized as a commercially available product or by a known method [for example, Chemical and Pharmaceutical Bulletin, 55, 372-375 (2007)] or a method analogous thereto.

[Step 13]
Compound (XVIII) can be obtained by reacting compound (XVII) obtained in step 12 in the same manner as in step 2.

[Step 14]
Compound (IX) can be obtained by reacting Compound (XVIII) obtained in Step 13 and Compound (V) in the same manner as in Step 3.

[Step 15]
Compound (Ic) can be obtained by reacting compound (IX) obtained in step 14 and compound (X) in the same manner as in step 6.

Production method 6:
Among the compounds (I), the compound (Ie) in which A ¹ is the formula (A), A ² is the formula (B), and X is —X ¹ — is, for example, from the compound (IV): It can also be obtained by the production method shown.

Wherein R ¹ , R ² , R ³ , R ⁴ , W, Y, Z ¹ , Z ² , Z ³ , Z ⁴ and Het are as defined above, and R ^b is a hydrogen atom or substituted even if an alkyl group, R ^c is an alkyl group which may be substituted, R ^d has the same meaning as a group capable of substituting for a hydrogen atom or X ^1, X 1 ^'is a substituted C _1-7 alkylene, and Hal ^a is a chlorine atom or a bromine atom.)

[Step 16]
Compound (XX) can be obtained by reacting compound (IV) obtained in step 2 with compound (XIX) in the same manner as in step 3.

[Step 17]
Compound (XXI) can be obtained by reacting compound (XX) obtained in step 16 with 0.1 to 5 equivalents, preferably 0.1 to 1 equivalents of an acid in a solvent.

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, acetone, methyl ethyl ketone, diethyl ketone, cyclohexanone, water or the like may be used alone or in combination. Among them, a mixed solvent of acetone and water is preferable.
Examples of the acid include organic sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid and camphorsulfonic acid, organic carboxylic acids such as acetic acid and trifluoroacetic acid, mineral acids such as hydrochloric acid and sulfuric acid, scandium trifluoromethanesulfonate, indium trifluoro Lewis acids such as romethanesulfonate can be raised, and p-toluenesulfonic acid is preferred among them. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at room temperature to 80 ° C., usually for 0.5 to 24 hours.

[Step 18]
Compound (XXI) obtained in Step 17 is added in a solvent in the presence of 1 to 10 equivalents, preferably 2 to 3 equivalents of acid, 1 to 10 equivalents, preferably 2 to 4 equivalents of borohydride compound, and 1 Compound (XXIII) can be obtained by reacting with ˜10 equivalents, preferably 1.1 to 2 equivalents of compound (XXII).

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol , N-propanol, 2-propanol and the like can be used alone or as a mixture thereof, among which 1,2-dichloroethane or methanol is preferred.
As the acid, for example, carboxylic acids such as formic acid, propionic acid, acetic acid and trifluoroacetic acid, and mineral acids such as hydrochloric acid can be used, among which acetic acid is preferable.
As the borohydride compound, for example, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride and the like can be used, and among them, sodium cyanoborohydride or sodium triacetoxyborohydride is preferable.
The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at room temperature to 40 ° C., usually for 0.5 to 24 hours.

[Step 19]
Compound (Ie) can be obtained by reacting compound (XXIII) obtained in step 18 with compound (VII) in the same manner as in step 4.

Production method 7:
Among the compounds (I), the compound (If) in which A ¹ is the formula (A), A ² is the formula (B), and W is methylene or methine is, for example, from the compound (VI-a): It can obtain by the manufacturing method shown in.

(Wherein R ¹ , R ² , R ³ , R ⁴ , X, Y, Z ¹ , Z ² , Z ³ , Z ⁴ and Het are as defined above. R ^b is a hydrogen atom or substituted. An optionally _substituted alkyl group, R ^e is a hydrogen atom or C _1-3 alkyl, and Hal ^a represents a chlorine atom or a bromine atom.)

[Step 20]
Compound (XXV) can be obtained by reacting compound (VI-a) obtained in Production Method 1 with compound (XXIV) in the same manner as in Step 4.

[Step 21]
Compound (If) can be obtained by reacting compound (XXV) obtained in step 20 with compound (XXVI) in the same manner as in step 18. A compound in which A ¹ is the formula (B) and A ² is the formula (A) can also be obtained from the compound (VI-b) obtained in Step 3 by the same production method.

Production method 8:
Of compound (I), compound (Ig) or compound (Ia) in which R ⁴ is a hydrogen atom can be obtained from compound (VI-a) by the production method shown below.

(Wherein R ¹ , R ² , R ³ , R ⁴ , W, X, Y, Z ¹ to Z ³ , Z ⁴ and Het are as defined above. R ^b is a hydrogen atom or substituted. Pro is a common amine protecting group shown in the literature (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)), and Hal ^a is a chlorine atom. Or a bromine atom.)

[Step 22]
Compound (XXVIII) can be obtained by reacting compound (VI-a) obtained in Production Method 1 with compound (XXVII) in the same manner as in Step 4.

[Step 23]
Compound (Ig) can be obtained by deprotecting the protecting group of compound (XXVIII) obtained in step 22. For example, when the protecting group is a Boc group, compound (Ig) can be obtained by reacting with an excess amount, preferably 5 to 10 equivalents of an acid in a solvent.

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, diethyl ether, dichloromethane, DCE, methanol, ethanol and the like are used alone or They can be used as a mixture. Among them, 1,4-dioxane, dichloromethane or methanol is preferable.
As the acid, for example, carboxylic acids such as formic acid, propionic acid, acetic acid and trifluoroacetic acid, and mineral acids such as hydrochloric acid can be used, among which hydrochloric acid or trifluoroacetic acid is preferable. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at room temperature to 40 ° C., usually for 0.5 to 24 hours.

[Step 24]
Compound (Ia) can be obtained by reacting compound (Ig) obtained in step 23 with the corresponding aldehyde or ketone derivative in the same manner as in step 18. A compound in which A ¹ is the formula (B) and A ² is the formula (A) can also be obtained from the compound (VI-b) obtained in Step 3 by the same production method.

Production method 9:
Among the compounds (I), ^{Z 1} is optionally substituted _{C 1-5} alkoxy ^group, with _{C 1-5} alkyl substituted with -NR ⁹ R 10, 4 ~ 10-membered nitrogen-containing saturated heterocyclic ring, Certain compounds (Ih) and (Ii) can be obtained from compound (XXIX) by the production method shown below.

(Wherein R ¹ , R ² , R ³ , R ⁴ , W, X, Y, Z ² to Z ⁴ and Het are as defined above. R ^b is a hydrogen atom or an optionally substituted alkyl. Hal ^a and Hal ^c are each independently a chlorine atom or a bromine atom, Z ^{1 ′} is C _1-5 alkylene, V is an optionally substituted C _1-5 alkoxy group, — NR ⁹ R ¹⁰ , a 4- to 10-membered nitrogen-containing saturated heterocyclic ring, etc., and R ⁹ and R ¹⁰ are as defined above.)

[Step 25]
For example, compound (XXX-a) or compound (XXX-b) is obtained by reacting compound (XXIX) obtained by a method according to WO 2005/110416 and compound (V) in the same manner as in Step 3. be able to.

[Step 26]
The compound (XXX-a) or the compound (XXX-b) obtained in the step 25 is 1 to 20 equivalents, preferably 1 to 20 equivalents, preferably 2 to 5 equivalents of a base in a solvent in the presence of a base. Is reacted with 3 to 10 equivalents of compound (XXXI) to give compound (XXXII-a) or compound (XXXII-b).

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, DMA, NMP, methanol , Ethanol, 1-propanol, 2-propanol and the like can be used alone or in admixture thereof, and among them, THF, 1,4-dioxane or DMF is preferable.
Examples of the base include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium acetate, inorganic bases such as sodium hydroxide and potassium hydroxide, aromatic amines such as pyridine and lutidine, triethylamine and tripropylamine. Tertiary amines such as tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-diisopropylethylamine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, Alkali metal hydrides such as sodium hydride and potassium hydride, among them, potassium carbonate, triethylamine or N, N-diisopropylethylamine are preferred.
The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably 20 to 80 ° C., usually for 0.5 to 24 hours.

[Step 27]
Compound (Ih) or Compound (Ii) can be obtained by reacting Compound (XXXII-a) or Compound (XXXII-b) obtained in Step 26 with Compound (VII) in the same manner as in Step 4. it can.

Production method 10:
Among compounds (I), compound (Ia) can also be obtained from compound (XXXIII) by the production method shown below.

(Wherein R ¹ , R ² , R ³ , R ⁴ , W, X, Y, Z ¹ to Z ⁴ and Het are as defined above. R ^b represents a hydrogen atom or an optionally substituted alkyl. Hal ^a is a chlorine atom or a bromine atom, and Hal ^d is a chlorine atom, a bromine atom or an iodine atom.)

[Step 28]
By reacting a commercially available product or a compound (XXXIII) synthesized according to the method described in, for example, Angewandte Chemie International Edition, 45, 7262-7265 (2006), and compound (V) in the same manner as in Step 3, Compound (XXXIV) can be obtained.

[Step 29]
Compound (XXXV) can be obtained by reacting compound (XXXIV) obtained in step 28 with compound (VII) in the same manner as in step 4.

[Step 30]
Compound (XXXV) obtained in Step 29 is added in the presence of 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of palladium catalyst in a solvent, and 1 to 5 equivalents, preferably 1.1 to 2 equivalents. Compound (Ia) can be obtained by reacting with an equivalent amount of compound (XXXVI) or compound (XXXVII).

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF and the like are used alone or in combination. And THF can be used.
Examples of the palladium catalyst include zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis A divalent catalyst such as (diphenylphosphinoferrocene) palladium dichloride can be used, and tetrakistriphenylphosphine palladium or bis (t-butylphosphine) palladium is particularly preferable. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at 20-100 ° C. or under microwave irradiation, usually for 0.5-24 hours.

Production method 11:
Among compounds (I), compound (Ia) can also be obtained from compound (XXXVIII) by the production method shown below.

(Wherein R ¹ , R ² , R ³ , R ⁴ , W, X, Y, Z ¹ to Z ⁴ and Het are as defined above. R ^b is a hydrogen atom or an optionally substituted alkyl. Hal ^a is a chlorine atom or bromine atom, Hal ^d is a chlorine atom, bromine atom or iodine atom, and Hal ^e is a bromine atom or iodine atom.)

[Step 31]
By reacting a commercially available product or a compound (XXXVIII) synthesized according to the method described in, for example, Organic and Biomolecular Chemistry, 1, 3353-3361 (2003), with compound (V) in the same manner as in Step 3, Compound (XXXIX) can be obtained.

[Step 32]
Compound (XXXXXX) can be obtained by reacting compound (XXXIX) obtained in step 31 with a halogenating agent in an amount of 1 to 5 equivalents, preferably 1.2 to 3 equivalents in a solvent.

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, benzene, toluene, xylene acetic acid, trifluoroacetic acid and the like are used alone. Or a mixture thereof, among which acetic acid is preferred.
Examples of the halogenating agent include halogenated imides such as N-bromosuccinimide, N-iodosuccinimide, and N-iodophthalimide, bromine or iodine, among which N-iodosuccinimide is preferable.
The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably 0-60 ° C., usually for 0.5-24 hours.

[Step 33]
Compound (VI-a) can be obtained by reacting compound (XXXX) obtained in step 32 with compound (XXXXI) or compound (XXXXII) in the same manner as in step 30.

[Step 34]
Compound (Ia) can be obtained by reacting compound (VI-a) obtained in step 33 with compound (VII) in the same manner as in step 4.

Production method 12:
Among compounds (I), compound (Ij) in which Het is a divalent group of thiazole can be obtained from compound (VI-a) by the production method shown below.

(Wherein R ¹ , R ² , R ³ , R ⁴ , W, X, Y, Z ¹ to Z ³ have the same meanings as described above. R ^f and R ^g may be independently substituted. A good alkyl, Hal ^a is a chlorine or bromine atom, and Hal ^f is a chlorine, bromine or iodine atom.)

[Step 35]
Compound (VI-a) obtained in Production Method 1 is 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalent of palladium catalyst in a solvent, optionally 0.01 to 1 equivalent, preferably Can be reacted with 1 to 5 equivalents, preferably 1.1 to 2 equivalents of compound (XXXXIII) in the presence of 0.05 to 0.2 equivalents of a phosphine ligand to give compound (XXXXIV). it can.
The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF can be used. Of these, toluene is preferred.
Examples of the palladium catalyst include zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis A divalent catalyst such as (diphenylphosphinoferrocene) palladium dichloride can be used, among which tetrakistriphenylphosphine palladium or palladium acetate is preferred.
Examples of phosphine ligands include monodentate ligands such as o-tolylphosphine, S-Phos or X-Phos, DPPF, DPPE, DPPP, DPPB, BINAP, XANT-Phos or DPE-Phos. The following bidentate ligands can be used, and S-Phos or X-Phos is particularly preferable.
The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at 50 to 180 ° C. or under microwave irradiation, usually for 0.5 to 24 hours.

[Step 36]
Compound (XXXXV) can be obtained by reacting Compound (XXXXIV) obtained in Step 35 with 1 to 5 equivalents, preferably 1.2 to 3 equivalents of a halogenating agent in a solvent.
The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, water and the like are used alone. Or they can be mixed and used, and a mixed solvent of THF and water is particularly preferable.
Examples of the halogenating agent include halogenated imides such as N-bromosuccinimide, N-iodosuccinimide, and N-iodophthalimide, bromine or iodine, among which N-bromosuccinimide is preferable.
The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably 0-40 ° C., usually for 0.5-24 hours.

[Step 37]
Compound (Ij) can be obtained by reacting Compound (XXXXV) obtained in Step 36 with 1 to 5 equivalents, preferably 1.2 to 3 equivalents of Compound (XXXXVI) in a solvent.
The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, methanol, ethanol, 1-propanol, 2-propanol, THF, 1,4-dioxane, DME, benzene , Toluene, xylene, DMF, water and the like can be used alone or in admixture thereof, with ethanol being preferred.
The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 90 ° C., usually for 0.5 to 24 hours. A compound in which A ¹ is the formula (B) and A ² is the formula (A) can also be obtained from the compound (VI-b) obtained in Step 3 by the same production method.

The compound of the present invention having a desired functional group at a desired position can be obtained by appropriately combining the above production methods. Isolation and purification of intermediates and products in the above production method may be performed by appropriately combining methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various chromatography, and the like. it can. In addition, the intermediate can be subjected to the next reaction without any particular purification.
The raw material compound or intermediate in the above production method may exist in the form of a salt such as hydrochloride depending on the reaction conditions and the like, 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 it is desired to use or obtain the raw material compound or intermediate in a free form, these are dissolved or suspended in an appropriate solvent, and a base such as an aqueous sodium hydrogen carbonate solution is obtained. It can be converted to the free form by neutralizing with, for example.

Among compounds (I) or pharmacologically acceptable salts thereof, there may exist isomers such as tautomers such as ketoenol, positional isomers, geometric isomers or optical isomers However, all possible isomers including these and mixtures in any ratio of the isomers are also encompassed by the present invention.
In addition, optical isomers can be separated by performing a known separation step such as a method using an optically active column or a fractional crystallization method in an appropriate step of the production method. An optically active substance can also be used as a starting material.

When the salt of compound (I) is desired to be obtained, the salt of compound (I) can be purified as it is, and when compound (I) is obtained in a free form, compound (I) is appropriately converted. A salt may be formed by dissolving or suspending in a solvent and adding an acid or a base. In addition, Compound (I) or a pharmaceutically acceptable salt thereof may exist in the form of a solvate with water or various solvents, and these solvates are also encompassed in the present invention.

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

As the administration route, it is desirable to use the most effective treatment, and oral or parenteral such as intravenous, application, inhalation and eye drop can be mentioned, preferably intravenous administration, It is particularly preferable to administer by intravenous infusion. Examples of the dosage form include tablets, injections and the like, with injections being preferred. The dosage and frequency of administration of these pharmaceutical compositions vary depending on the dosage form, the patient's disease and symptoms, the patient's age and weight, etc., and cannot be generally specified, but are usually effective for adults per day The amount of the component is in the range of about 0.0001 to about 2000 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, particularly preferably in the range of about 1 to about 300 mg. It can be administered once or several times a day.

Hereinafter, the present invention will be described more specifically with reference to examples and reference examples, but the scope of the present invention is not limited to these examples.

The following physicochemical data of each compound in the examples was measured by the following instruments.
¹ HNMR: JEOL JNM-LA300
Each compound was purified using a high flash column (silica gel column or amino silica gel column) manufactured by Yamazen Corporation.

(Reference Example 1)
2-Chloro-5,6-dimethyl-N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine

(A) Phosphorus oxychloride (13 ml) was added to 2,4-dichloro-5,6-dimethylpyrimidine 5,6-dimethyluracil (2.0 g, 14.3 mmol), and the mixture was heated to reflux. After 2.5 hours, ice was added to the residue obtained by evaporation under reduced pressure, and the mixture was neutralized with an aqueous sodium hydroxide solution. This was subjected to separation / extraction with ethyl acetate, and the organic layer was washed with saturated brine and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to obtain Compound 1A (1.97 g, yield 78%).
¹ H-NMR (CDCl ₃ , δ ppm): 2.52 (3H, s), 2.32 (3H, s).

(B) 2-Chloro-5,6-dimethyl-N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine 2-propanol of compound 1A (1.51 g, 8.53 mmol) obtained above To the (45 ml) solution, N- (3-aminopropyl) pyrrolidine (2.16 mL, 17.1 mmol) and N, N-diisopropylethylamine (3.70 ml, 21.3 mmol) were added and stirred at 90 ° C. After 5 hours, the reaction solution was subjected to separation / extraction with ethyl acetate-water, and the organic layer was washed with saturated brine and evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 1B (1.86 g, yield 81%).
¹ H-NMR (CDCl ₃ , δ ppm): 7.73 (1H, brs), 3.49-3.58 (2H, m), 2.64-2.71 (2H, m), 2.49-2.60 (4H, m), 2.28 (3H, s), 1.87 (3H, s), 1.73-1.82 (6H, m).

Reference Example 2-4 :
The corresponding starting materials were used and reacted and treated in the same manner as described in Reference Example 1 to obtain the compounds shown in Table 1.

(Reference Example 5)
tert-Butyl 4- (4- (4,5-dimethyl-6- (3- (2-oxopyrrolidin-1-yl) propylamino) pyrimidin-2-yl) thiazol-2-yl) piperidine-1-carboxy rate

(A) 1- (3- (2-Chloro-5,6-dimethylpyrimidin-4-ylamino) propyl) pyrrolidin-2-one Compound 1A obtained in Reference Example 1 (1.0 g, 5.65 mmol) in isopropanol (30 ml) 1- (3-Aminopropyl) -2-pyrrolidinone (1.58 ml, 11.3 mmol) and N, N-diisopropylethylamine (1.97 ml, 11.3 mmol) were added to the solution, and the mixture was stirred at 80 ° C. After 5 hours, the reaction solution was subjected to separation / extraction with chloroform-water, and the organic layer was washed with saturated brine and evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; ethyl acetate: hexane) to obtain Compound 2A (1.40 g, yield 88%).
¹ H-NMR (CDCl ₃ , δ ppm): 6.43-6.51 (1H, m), 3.33-3.46 (6H, m), 2.44 (2H, t, J = 8.1 Hz), 2.31 (3H, s), 2.02 -2.12 (5H, m), 1.68-1.76 (2H, m).

(B) 1- (3- (2- (1-ethoxyvinyl) -5,6-dimethylpyrimidin-4-ylamino) propyl) pyrrolidin-2-one Compound 2A obtained above (799 mg, 2.83 mmol) To a toluene solution (6 ml) of tributyl (1-ethoxyvinyl) tin (1.33 g, 3.67 mmol), palladium acetate (63.5 mg, 0.283 mmol), S-Phos (232.3 mg, 0.566 mmol), and microwave. Stir at 140 degrees under irradiation. After 1.5 hours, liquid separation and extraction were performed with chloroform-water, and the organic layer was washed with saturated brine and then distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: chloroform) to obtain Compound 2B (312 mg, yield 35%).
¹ H-NMR (CDCl ₃ , δ ppm): 5.90-5.96 (1H, m), 5.44 (1H, d, J = 1.5 Hz), 4.39 (1H, d, J = 1.2 Hz), 3.95 (2H, q , J = 7.2 Hz), 3.45-3.51 (2H, m), 3.34-3.41 (4H, m), 2.38-2.44 (5H, m), 1.99-2.09 (5H, m), 1.75-1.80 (2H, m ), 1.45 (3H, t, J = 7.2 Hz).

(C) tert-butyl 4- (4- (4,5-dimethyl-6- (3- (2-oxopyrrolidin-1-yl) propylamino) pyrimidin-2-yl) thiazol-2-yl) piperidine- 1-Carboxylate To a solution of compound 2B (397 mg, 1.25 mmol) obtained above in tetrahydrofuran (6 ml) and water (0.3 mL), N-bromosuccinimide (200.3 mg, 1.13 mmol) was added under ice cooling. And stirred. After 2 hours, the mixture was subjected to separation / extraction with chloroform-water, and the organic layer was washed with saturated brine and evaporated under reduced pressure. To an ethanol solution (10 mL) of the obtained crude product, tert-butyl 4-carbamothioylpiperidine-1-carboxylate (458 mg, 1.88 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Stirring under. After 2 hours, the reaction solution was allowed to cool at room temperature and concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 2C (204 mg, yield 32%).
¹ H-NMR (CDCl ₃ , δ ppm): 8.01 (1H, s), 5.99-6.02 (1H, m), 4.15-4.25 (1H, m), 3.51-3.57 (2H, m), 3.30-3.42 ( 6H, m), 2.77-2.85 (2H, m), 2.40-2.46 (5H, m), 2.00-2.16 (7H, m), 1.75-1.83 (2H, m), 1.66-1.71 (2H, m), 1.45 (9H, s).

(Reference Example 6)
tert-butyl 4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) thiazol-2-yl) piperazine-1-carboxylate

For example, a solution of compound 3A (1.45 g, 4.16 mmol) synthesized by the method described in WO 2006/072436 in tetrahydrofuran (25 ml) is cooled to −78 ° C., and 1.65 M butyllithium hexane solution (3.15 ml, 5.20 mmol) is added. It was dripped. After 1.5 hours, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.01 g, 5.41 mmol) was added and stirred for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction. Liquid separation extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, and then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound (1.99 g, yield 65%).
¹ H-NMR (CDCl ₃ , δ ppm): 7.65 (1H, s), 3.47-3.57 (8H, m), 1.46 (9H, s), 1.30 (12H, s).

(Reference Example 7)
tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

For example, the title compound was obtained by synthesizing in the same manner as in Reference Example 6 using compound 4A synthesized by the method described in WO 2009/045992 (630 mg, yield 41%).
¹ H-NMR (CDCl ₃ , δ ppm): 7.77 (1H, s), 7.71 (1H, s), 4.16-4.33 (3H, m), 2.78-2.92 (2H, m), 2.06-2.15 (2H, m), 1.79-1.96 (2H, m), 1.45 (9H, s), 1.29 (12H, s).

(Reference Example 9)
1- (3- (5,6-Dimethyl-2- (2- (4-methylpiperazin-1-yl) thiazolo-4-yl) pyrimidin-4-ylamino) propyl) pyrrolidin-2-one

(A) tert-butyl 4- (4- (4,5-dimethyl-6- (3- (2-oxopyrrolidin-1-yl) propylamino) pyrimidin-2-yl) thiazol-2-yl) piperidine- 1-Carboxylate The title compound was obtained by synthesis using the compound obtained in Example 5 (c) in the same manner as in Reference Example 5 (c) (yield 67%).
¹ H-NMR (CDCl ₃ , δ ppm): 7.45 (1H, s), 5.95-6.02 (1H, m), 3.46-3.57 (10H, m), 3.32-3.42 (4H, m), 2.36-2.45 ( 5H, m), 1.97-2.08 (5H, m), 1.72-1.81 (2H, m), 1.44 (9H, s).

(B) 1- (3- (5,6-Dimethyl-2- (2- (piperazin-1-yl) thiazolo-4-yl) pyrimidin-4-ylamino) propyl) pyrrolidin-2-one obtained above To a methanol solution (3 ml) of Compound 6A (300 mg, 0.58 mmol) was added 4 mol / l-dioxane hydrochloride (1.5 ml), and the mixture was stirred at room temperature. After stirring overnight, the mixture was quenched with aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (241 mg, yield 100%).
¹ H-NMR (CDCl ₃ , δ ppm): 7.44 (1H, s), 5.93-6.01 (1H, m), 3.49-3.61 (6H, m), 3.33-3.43 (4H, m), 2.95-3.03 ( 4H, m), 2.34-2.48 (6H, m), 2.03-2.11 (4H, m), 1.74-1.86 (2H, m).

(C) 1- (3- (5,6-Dimethyl-2- (2- (4-methylpiperazin-1-yl) thiazolo-4-yl) pyrimidin-4-ylamino) propyl) pyrrolidin-2-one To a THF (5.0 ml) solution of the compound obtained in step (190 mg, 0.457 mmol), add sodium triacetoxyborohydride (290 mg, 1.37 mmol) and 35% aqueous formaldehyde solution (113 μl, 1.37 mmol) at room temperature. Stir. After 1.5 hours, an aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate-water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; ethyl acetate: hexane) to give the title compound (142 mg, yield 72%).
¹ H-NMR (CDCl ₃ , δ ppm): 7.47 (1H, s), 5.98-6.07 (1H, m), 3.57-3.65 (4H, m), 3.49-3.57 (2H, m), 3.33-3.42 ( 4H, m), 2.49-2.57 (4H, m), 2.38-2.46 (5H, m), 2.34 (3H, s), 2.08 (3H, s), 1.98-2.08 (2H, m), 1.74-1.84 ( 2H, m).

(Reference Example 10)
tert-butyl 4- (3- (4,5-dimethyl-6- (3- (pyrrolidin-1-yl) propylamino) pyrimidin-2-yl) -1H-indol-1-yl) piperidine-1-carboxy rate

(A) tert-butyl 4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indol-1-yl) piperidine-1-carboxylate To a solution of tert-butyl 4- (3-iodo-1H-indol-1-yl) piperidine-1-carboxylate (960 mg, 2.25 mmol) in N, N-dimethylformamide (8 ml), [1,1 ' -Bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (184 mg, 0.225 mmol), bis (pinacolato) diboron (857 mg, 3.38 mmol), potassium acetate (662 mg, 6.75 mmol), and 90 Heated to ° C. After 1.5 hours, water was added, followed by separation / extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; ethyl acetate: hexane) to give the title compound (111 mg, yield 12%).
¹ H-NMR (CDCl ₃ , δ ppm): 8.00-8.04 (1H, m), 7.63 (1H, s), 7.32-7.36 (1H, m), 7.13-7.22 (2H, m), 4.25-4.41 ( 3H, m), 2.83-2.95 (2H, m), 2.01-2.10 (2H, m), 1.85-1.94 (2H, m), 1.48 (9H, s), 1.34 (12H, s).

(B) tert-butyl 4- (3- (4,5-dimethyl-6- (3- (pyrrolidin-1-yl) propylamino) pyrimidin-2-yl) -1H-indol-1-yl) piperidine- 1-Carboxylate Compound 1B (53 mg, 0.197 mmol) obtained in Reference Example 1, 3 mol was added to a solution of compound 7A (111 mg, 0.260 mmol) obtained above in 1,4-dioxane (1.2 ml). / l Aqueous sodium carbonate (0.3 ml, 0.90 mmol) and tetrakistriphenylphosphine palladium (23.1 mg, 0.020 mmol) were added, and the mixture was stirred at 150 ° C. under microwave irradiation. After 1 hour, separation / extraction with chloroform-water was performed, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound (77.0 mg, yield 73%).
¹ H-NMR (CDCl ₃ , δ ppm): 8.69-8.73 (1H, m), 8.05 (1H, s), 7.33-7.38 (1H, m), 7.17-7.24 (2H, m), 6.77-6.83 ( 1H, m), 4.25-4.43 (3H, m), 3.71-3.77 (2H, m), 2.85-2.96 (2H, m), 2.67-2.73 (2H, m), 2.52-2.61 (4H, m), 2.39 (3H, s), 2.06-2.15 (2H, m), 1.86-2.01 (7H, m), 1.75-1.83 (4H, m), 1.48 (9H, s).

Example 1
5,6-Dimethyl-2- (4- (4-piperazin-1-yl) thiazol-5-yl) -N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine

To a solution of the compound obtained in Reference Example 1 (100 mg, 0.372 mmol) in 1,4-dioxane (1.5 ml) and water (0.37 ml), the compound obtained in Reference Example 6 (331 mg, 0.670 mmol), 3M- Aqueous sodium carbonate (0.37 ml, 1.11 mmol) and tetrakistriphenylphosphine palladium (43.0 mg, 0.037 mmol) were added, and the mixture was stirred at 140 ° C. under microwave irradiation. After 1 hour, separation / extraction with chloroform-water was performed, and the organic layer was washed with saturated brine and evaporated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate: chloroform). A 4N-hydrochloric acid methanol solution (1.0 ml, 4.0 mmol) was added to a methanol (1 ml) solution of the obtained crude product, and the mixture was stirred at room temperature for 5.5 hours. Liquid separation extraction was performed with ethyl acetate-hydrochloric acid, and the aqueous layer was adjusted to pH = 10 with an aqueous sodium hydroxide solution. This was subjected to separation / extraction with chloroform, and the organic layer was washed with saturated brine and then distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; ethyl acetate: chloroform) to obtain the title compound (75.9 mg, yield 51% (2 steps)).
¹ H-NMR (CDCl ₃ , δ ppm): 7.91 (1H, s), 6.84-6.90 (1H, m), 3.54-3.62 (2H, m), 3.47-3.54 (4H, m), 2.93-3.01 ( 4H, m), 2.62-2.70 (2H, m), 2.50-2.58 (4H, m), 2.32 (3H, s), 1.91 (3H, s), 1.73-1.84 (6H, m).

Example 2 :
The corresponding starting materials were used and reacted in the same manner as in Example 1 to obtain the compounds shown in Table 2.

Example 4
N1- (5-methoxy-2- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) pyrimidin-4-yl) -N3, N3-dimethylpropane-1,3-diamine

To a solution of the compound obtained in Reference Example 2 (65.0 mg, 0.266 mmol) in 1,4-dioxane (1 ml) and water (1 ml), 1-methyl-4- (5- (4,4,5,5 -Tetramethyl-1,3,2-dioxaboran-2-yl) pyridin-2-yl) piperazine (121 mg, 0.398 mmol), sodium carbonate (84 mg, 0.797 mmol), tetrakistriphenylphosphine palladium (15.4 mg, 0.013 mmol) was added, and the mixture was stirred at 120 ° C. under microwave irradiation. After 1.5 hours, separation and extraction were performed with chloroform-water, and the organic layer was washed with saturated brine and then distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate: chloroform) to give the title compound (57.0 mg, yield 56%).
¹ H-NMR (CDCl ₃ , δ ppm): 9.13 (1H, d, J = 2.4 Hz), 8.34 (1H, dd, J = 2.4,9.0 Hz), 7.70 (1H, s), 6.65 (1H, d , J = 9.0 Hz), 6.02-6.08 (1H, m), 3.84 (3H, s), 3.57-3.64 (6H, m), 2.49-2.52 (4H, m), 2.39 (2H, t, J = 6.6 Hz), 2.32 (3H, s), 2.22 (6H, s), 1.77-1.84 (2H, m).

Example 5-6 :
The corresponding starting materials were used and reacted and treated in the same manner as in Example 4 to obtain the compounds shown in Table 3.

(Example 7)
5,6-Dimethyl-2- (2- (4-methylpiperazin-1-yl) thiazol-5-yl) -N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine

To a solution of the compound obtained in Example 1 (55.1 mg, 0.137 mmol) in methanol (1 ml), acetic acid (6 μl), formaldehyde (33.9 μl, 0.411 mmol), sodium cyanoborohydride (25.8 mg, 0.411 mmol) were added. The mixture was added and stirred at room temperature. After 4 hours, an aqueous sodium hydroxide solution was added, followed by separation / extraction with chloroform, and the organic layer was washed with saturated brine and evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; ethyl acetate: chloroform) to give the title compound (25.7 mg, yield 45%).
¹ H-NMR (CDCl ₃ , δ ppm): 7.90 (1H, s), 6.81-6.87 (1H, m), 3.52-3.62 (6H, m), 2.63-2.69 (2H, m), 2.45-2.59 ( 8H, m), 2.33 (3H, s), 2.32 (3H, s), 1.91 (3H, s), 1.75-1.85 (6H, m).

Example 9
5,6-Dimethyl-2- (2- (1-methylpiperidin-4-yl) thiazol-4-yl) -N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine

Lithium aluminum hydride (73 mg, 1.93 mmol) was added to a THF (5 ml) solution of compound 2C (198 mg, 0.385 mmol) obtained in Reference Example 5, and the mixture was stirred at room temperature for 1.5 hours and then heated to reflux. After 4 hours, separation / extraction with chloroform-aqueous sodium hydroxide solution was performed, and the organic layer was washed with saturated brine and evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; ethyl acetate: chloroform) to give the title compound (47.9 mg, yield 30%).
¹ H-NMR (CDCl ₃ , δ ppm): 8.02 (1H, s), 7.06-7.10 (1H, m), 3.62-3.67 (2H, m), 3.15-3.23 (1H, m), 2.91-2.95 ( 2H, m), 2.66-2.69 (2H, m), 2.51-2.59 (4H, m), 2.43 (3H, s), 2.29 (3H, s), 2.14-2.19 (2H, m), 2.00-2.08 ( 2H, m), 1.95 (3H, s), 1.78-1.89 (8H, m).

(Example 10)
5,6-Dimethyl-2- (2- (4-methylpiperazin-1-yl) thiazol-4-yl) -N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine

Lithium aluminum hydride (24.7 mg, 0.652 mmol) was added to a THF (5 ml) solution of compound 6C (70.0 mg, 0.163 mmol) obtained in Reference Example 9, and the mixture was stirred at room temperature. After 2 hours, separation / extraction with chloroform-aqueous sodium hydroxide solution was performed, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; ethyl acetate: hexane) to give the title compound (22.2 mg, yield 33%).
¹ H-NMR (CDCl ₃ , δ ppm): 7.43 (1H, s), 6.77-6.89 (1H, m), 3.65-3.73 (2H, m), 3.55-3.62 (4H, m), 2.58-2.90 ( 6H, m), 2.46-2.55 (4H, m), 2.40 (3H, s), 2.33 (3H, s), 1.98 (3H, s), 1.81-1.97 (6H, m).

(Example 11)
5,6-Dimethyl-2- (1- (1-methylpiperidin-4-yl) -1H-indol-3-yl) -N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine

Lithium aluminum hydride (34.1 mg, 0.90 mmol) was added to a THF (2 ml) solution of compound 7B (60.0 mg, 0.113 mmol) obtained in Reference Example 10, and the mixture was heated to reflux. After 5 hours, separation / extraction with chloroform-aqueous sodium hydroxide solution was performed, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; ethyl acetate: hexane) to give the title compound (10.1 mg, yield 20%).
¹ H-NMR (CDCl ₃ , δ ppm): 8.69-8.73 (1H, m), 8.09 (1H, s), 7.34-7.38 (1H, m), 7.15-7.23 (2H, m), 6.73-6.78 ( 1H, m), 4.17-4.26 (1H, m), 3.69-3.77 (2H, m), 2.99-3.07 (2H, m), 2.66-2.73 (2H, m), 2.52-2.61 (4H, m), 2.39 (3H, s), 2.35 (3H, s), 2.05-2.22 (6H, m), 1.96 (3H, s), 1.86-1.92 (2H, m), 1.75-1.83 (4H, m).

Next, the pharmacological action of a representative compound of the present invention will be specifically described with reference to test examples.
Test Example 1 : Human TLR ⁹ Reporter Gene Test A HEK293 cell stable human TLR ⁹ expression strain (human TLR ⁹ -293 cell) was asleep and the passage was repeated until the cell state was stabilized. The cell culture was left in a CO ₂ incubator (37 ° C., 5% CO ₂ ). For cell recovery, the cells were detached using trypsin-EDTA, and the cell pellet after centrifugation was suspended in a growth medium. Human TLR ⁹ -293 cells prepared to 3 × 10 ⁵ cells / mL were seeded on a 6-well collagen plate and cultured overnight. The NF-κB-luciferase gene was introduced into the cells and cultured overnight. NF-κB-luciferase gene-introduced cells were prepared at 6.25 × 10 ⁵ cells / mL, and seeded in a 96-well black plate at 80 μL / well (5 × 10 ⁴ cells / well). Add 10 μL each of test substance (final concentration: 1, 3, 10, 30, 100, 300, 1000 nM) and CpG2006 (5′-TCG TCG TTT TGT GGT TTT GTC GTT-3 ′) (final concentration 150 nM) Thereafter, the cells were cultured for 6 hours. Bright-Glo preparation solution was added at 100 μL / well and allowed to stand for 1 minute in the dark. Luminescence was measured using a luminometer, and the 50% inhibition rate (IC ₅₀ value) of each test substance was calculated and shown in Table 4.

As shown in Table 4, the compound of the present invention exhibited a strong inhibitory action in the NF-kB inhibition test. The compounds of Examples 1, 9, 10, and 11 showed particularly strong inhibitory action.

Test Example 2 : CpG-induced IL-6 production inhibition test using mouse spleen cells Mouse spleen cells were prepared as follows. The spleen removed from C57BL / 6 mice (♀) was divided with surgical scissors and ground with a slide of a slide glass. After centrifugation, hemolysis was performed using ACK. Medium was added to stop the ACK reaction, and centrifugation was performed. The cells were prepared to 1 × 10 ⁷ cells / mL and seeded in a 96-well plate at 100 μL / well (1 × 10 ⁶ cells / well). Add 50 μL each of the test substance (final concentration: 1, 3, 10, 30, 100, 300, 1000 nM) and CpG1826 (5′-TCC ATG ACG TTC CTG ACG TT -3 ′) (final concentration 100 nM). _The cells were cultured in a ₂ incubator (37 ° C., 5% CO ₂ ) for 24 hours. The amount of IL-6 produced in the culture supernatant was measured using an ELISA kit, and the 50% inhibition rate (IC ₅₀ value) of each test substance was calculated and shown in Table 5.

As shown in Table 5, the compound of the present invention exhibited a strong inhibitory action in the IL-6 production inhibition test. In addition, the compounds that showed high activity values in the NF-kB inhibition test shown in Table 5 also showed a strong IL-6 production inhibitory action as in the above Examples.

Test Example 3 : Drug efficacy evaluation test using CpG1826 administration model (peritoneal administration) A CpG1826 solution was administered intraperitoneally to mice under ether anesthesia. One to six hours after administration of CpG1826, blood was collected under ether anesthesia and peritoneal lavage fluid was collected. Blood was collected from the heart and collected in a tube containing heparin, and abdominal cavity washing was collected after injecting PBS (phosphate buffered saline) into the abdominal cavity to massage the abdomen. The compound was administered from the mouse tail vein before CpG1826 administration. The blood was made into plasma by centrifugation, and cytokine was measured by a commercially available ELISA kit. The amount of IL-6 produced was measured, and the inhibition rate (%) was calculated by comparison with the solvent control of each test substance. The compound of Example 7 had an IL-6 production inhibition ED ₅₀ = 6.2 (mg / kg).
In Example 7, administration 2 hours after CpG1826 administration, significant suppression of inflammatory cytokine production can be confirmed as compared with the solvent control group, and the compound of the present invention suppresses TLR ^9- dependent inflammatory cytokine production. Indicated.

As described above, the derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, prevents and / or treats an autoimmune disease, specifically, a disease in which an autoimmune disease is involved ( It can be used as a preventive and / or therapeutic agent for inflammation, allergy, asthma, graft rejection, graft-versus-host disease, infection, cancer), immunodeficiency or neurodegenerative disease (Alzheimer, Parkinson's disease, etc.). Further, by finding a TLR inhibitor that selectively inhibits TLR, it can be used as a pharmaceutical effective for the prevention and / or treatment of sepsis, particularly severe sepsis.

Claims

Formula (I):

[Wherein, A 1 and A 2 represent the following formula (A) or (B),

When A 1 is Formula (A), A 2 represents formula (B),
When A 1 is Formula (B), A 2 represents formula (A),
X is, -X 1 -, - X 1 -NR 5 CO-X 2 -, - X 1 -CONR 5 -X 2 -, - X 1 -CO-X 2 -, - X 1 -NR 6 CONR 5 - X 2- , -X 1 -NR 5 -X 2 -or -X 1 -O-X 2-
X 1 represents an optionally substituted C 1-8 alkylene, and when X is —X 1 —, X 1 is an unsubstituted C 2-3 alkylene or an optionally substituted C 4 -8 alkylene, and X is -X 1 -NR 5 CO-X 2- , -X 1 -NR 6 CONR 5 -X 2- , -X 1 -NR 5 -X 2 -or -X 1 -O- When X 2 —, X 1 is an optionally substituted C 2-8 alkylene;
X 2 represents an optionally substituted C 1-8 alkylene, wherein X represents —X 1 —CONR 5 —X 2 —, —X 1 —NR 6 CONR 5 —X 2 —, —X When 1 —NR 5 —X 2 — or —X 1 —O—X 2 —, X 2 is an optionally substituted C 2-8 alkylene;
Y represents a hydrogen atom, an optionally substituted C 1-10 alkyl or an optionally substituted C 3-8 cycloalkyl,
Het represents a 5-6 membered nitrogen-containing heteroarylene,
W represents —W 1 —, —NR 7 —W 1 —, —NR 7 CO—W 1 —, —CONR 7 —W 1 — or —O—W 1 —,
Here, when W is bonded to a nitrogen atom on the Het ring, W represents —W 1 — or —CONR 7 —W 1 —,
W 1 represents an optionally substituted C 1-8 alkylene, and when W is —NR 7 —W 1 —, —CONR 7 —W 1 — or —O—W 1 —, W 1 is Optionally substituted C 2-8 alkylene,
Z 1 and Z 2 are each independently a hydrogen atom; an optionally substituted C 1-10 alkyl; an optionally substituted C 3-8 cycloalkyl; a cyano; an optionally substituted C 1 Represents -5 alkoxycarbonyl-; optionally substituted heteroaryl; halogen; optionally substituted C 1-5 alkoxy; or —NR 8 R 9 ,
Z 3 and Z 4 each independently represent a hydrogen atom; an optionally substituted C 1-10 alkyl; a halogen; or an optionally substituted C 1-5 alkoxy, or Z 3 and Z 4 May form a 5- to 8-membered saturated or unsaturated heterocyclic ring or saturated or unsaturated carbocyclic ring which may be substituted together when they are adjacent to each other,
R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, an optionally substituted C 1-10 alkyl, an optionally substituted C 3-8 cycloalkyl or a substituted Represents a 4-10 membered saturated heterocycle,
R 5 , R 6 , R 7 , R 8 and R 9 each independently represents a hydrogen atom or an optionally substituted C 1-10 alkyl;
R 1 -R 2 , X 1 -Y, R 1 -R 5 , R 5 -X 2 , R 1 -X 1 , R 1 -X 2 , R 3 -R 4 , R 3 -R 7 , R 3- Each group of W 1 or R 7 -W 1 is a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atom of each group (the substituent of the ring is a ring (The number of nitrogen-containing saturated heterocycles formed is the same as that in formula (A) and formula (B), respectively). Independently, 0 to 2), wherein X is —X 1 —, and the carbon atoms of each group of the group of R 1 —X 1 may be bonded to each other to be substituted; when forming a nitrogen-containing saturated heterocycle 10-membered, X 1 is optionally C 4-8 alkylene optionally substituted, or, X 1 is n- propylene (However, the position of forming the rings are carbon atoms at position 1 or 3 of the n- propylene) is'
Or a pharmaceutically acceptable salt thereof.
The alkyl part of each group of optionally substituted alkyl, optionally substituted alkoxy and optionally substituted alkoxycarbonyl-
(1) a halogen atom,
(2) hydroxyl group,
(3) Cyano,
(4) carboxyl,
(5) optionally substituted C 3-8 cycloalkyl,
(6) aryl which may be substituted,
(7) optionally substituted heteroaryl,
(8) C 1-5 alkoxy or fluorine may be substituted with atoms C 1-5 alkoxy,
(9) optionally substituted C 3-8 cycloalkoxy,
(10) C 1-5 alkoxycarbonyl-,
(11) -NR 10 R 11 ,
(12) -CONR 10 R 11 ,
(13) an optionally substituted 4- to 10-membered saturated heterocyclic ring, and (14) an optionally substituted C 1-5 alkylcarbonyl-
May be substituted with the same or different 1 to 5 substituents selected from the group consisting of
The optionally substituted alkylene is selected from the group consisting of the above (1) to (14), and (15) C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms or hydroxyl groups. It may be substituted with 1 to 5 substituents which are the same or different (wherein the groups shown in the above (6) and (7) are
(A) a hydroxyl group,
(B) halogen,
(C) C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms or hydroxyl groups,
(D) C 1-5 alkoxy optionally substituted with 1 to 5 fluorine atoms or hydroxyl groups,
(E) cyano,
(F) carboxyl,
(G) -NR 10 R 11 ,
(H) -CONR 10 R 11 ,
(I) means a group optionally substituted by 1 to 5 substituents selected from the group consisting of C 1-5 alkoxycarbonyl-, and (j) C 1-5 alkylcarbonyl-. ,
The groups shown in (5), (9), (13) and (14) are the above (a) hydroxyl group,
(B) halogen,
(C) C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms or hydroxyl groups,
(D) C 1-5 alkoxy optionally substituted with 1 to 5 fluorine atoms or hydroxyl groups,
(H) -CONR 10 R 11 ,
(I) means a group optionally substituted by 1 to 5 substituents selected from the group consisting of C 1-5 alkoxycarbonyl-, and (j) C 1-5 alkylcarbonyl- );
The optionally substituted cycloalkyl (saturated carbocycle) and the optionally substituted saturated heterocycle are the above (a), (b), (c), (d), (h), (i) and A group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of (j);
The optionally substituted aryl (unsaturated carbocycle) and the optionally substituted heteroaryl (unsaturated heterocycle) are the same or different ones selected from the group consisting of the above (a) to (j); A group optionally substituted by 5 substituents;
R 10 and R 11 are each independently a hydrogen atom or C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, or R 10 and R 11 are taken together. A 4- to 10-membered nitrogen-containing saturated heterocyclic ring may be formed,
The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
When A 1 is formula (A), A 2 is formula (B),
When A 1 is formula (B), A 2 is formula (A),
X is, -X 1 -, - X 1 -NR 5 CO-X 2 -, - X 1 -CONR 5 -X 2 -, - X 1 -CO-X 2 -, - X 1 -NR 6 CONR 5 - X 2 —, —X 1 —NR 5 —X 2 — or —X 1 —O—X 2 —,
X 1 is C 1-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-10 alkyl, wherein X 1 When is —X 1 —, X 1 is unsubstituted C 2-3 alkylene, or substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-10 alkyl. C 4-8 alkylene, and X is —X 1 —NR 5 CO—X 2 —, —X 1 —NR 6 CONR 5 —X 2 —, —X 1 —NR 5 —X 2 —. Or, in the case of —X 1 —O—X 2 —, X 1 may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-10 alkyl. C 2-8 alkylene der ,
X 2 is C 2-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-10 alkyl;
Y is a hydrogen atom; a C 1-10 alkyl optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-3 alkoxy; or a hydroxyl group, fluorine C 3-8 cycloalkyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of an atom and C 1-3 alkoxy;
Het is a 5-6 membered heteroarylene containing a nitrogen atom,
W is —W 1 —, —NR 7 —W 1 —, —NR 7 CO—W 1 —, —CONR 7 —W 1 — or —O—W 1 —,
Here, when W is bonded to a nitrogen atom on the Het ring, W is —W 1 — or —CONR 7 —W 1 —,
W 1 is C 1-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-10 alkyl, wherein W 1 Is —NR 7 —W 1 —, —CONR 7 —W 1 —, or —O—W 1 —, W 1 is the same or different from 1 to 5 selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-10 alkyl C 2-8 alkylene optionally substituted with 3 substituents,
Z 1 and Z 2 are each independently a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is the same or different from 1 to 5 selected from the group consisting of C 1-5 alkoxy and a fluorine atom) 3 may be substituted with a substituent) and 4-10 membered nitrogen-containing saturated same or different 1 to 3 of which may be substituted with a substituent C 1 is selected from the group consisting of heterocyclic -10 alkyl; C 3-8 cycloalkyl optionally substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-5 alkoxy; cyano; 1-3 number of is C 1-5 optionally alkoxycarbonyl-substituted by fluorine atom -; halogen and C 1-10 alkyl (the group may also be substituted with one to three fluorine atoms) consisting of Heteroaryl optionally substituted with the same or different 1 to 3 substituents selected from: halogen; substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom C 1-5 alkoxy; or —NR 8 R 9 ,
Each of Z 3 and Z 4 independently represents a hydrogen atom; a C 1-10 alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom; halogen Or C 1-5 alkoxy optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom, or when Z 3 and Z 4 are adjacent to each other 5- to 8-membered saturated or unsaturated heterocyclic ring or saturated or unsaturated carbocyclic ring which may be substituted together (substituent of the ring may be substituted in each group constituting the ring) The same as a good substituent)
R 1 , R 2 , R 3 and R 4 are each independently the same or selected from the group consisting of a hydrogen atom; a hydroxyl group, a fluorine atom, C 1-5 alkoxy, C 1-5 alkylcarbonyl- and carbamoyl C 1-10 alkyl optionally substituted with 1 to 3 different substituents; C optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group and a fluorine atom 3-8 cycloalkyl; or 1-3 identical or different substituents selected from the group consisting of hydroxyl, fluorine, C 1-10 alkyl, C 1-5 alkoxycarbonyl- and C 1-5 alkylcarbonyl- A 4- to 10-membered saturated heterocyclic ring optionally substituted by
R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom, or the same or different 1 to 3 substituents selected from the group consisting of fluorine, hydroxyl group and C 1-5 alkoxy A C 1-10 alkyl optionally substituted with
R 1 -R 2 , X 1 -Y, R 1 -R 5 , R 5 -X 2 , R 1 -X 1 , R 1 -X 2 , R 3 -R 4 , R 3 -R 7 , R 3- Each group of W 1 or R 7 -W 1 is a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atom of each group (the substituent of the ring is a ring; (The number of nitrogen-containing saturated heterocycles formed is the same as that in formula (A) and formula (B), respectively). Independently, 0 to 2), wherein X is —X 1 —, and the carbon atoms of each group of the group of R 1 —X 1 may be bonded to each other to be substituted; When forming a 10-membered nitrogen-containing saturated heterocyclic ring, X 1 is the same as selected from the group consisting of a hydroxyl group, a fluorine atom, and C 1-10 alkyl. C 4-8 alkylene which may be substituted with one or three different substituents, or n-propylene (provided that the ring is formed at the 1- or 3-position carbon atom of n-propylene). And when the carbon atom of each group of the X 1 -Y group is bonded to form an optionally substituted 4- to 10-membered nitrogen-containing saturated heterocyclic ring, the nitrogen-containing saturated heterocyclic ring Is not morpholine,
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
A 1 is the formula (A), and A 2 is the formula (B).
The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
Z 1 and Z 2 are each independently a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is the same or different from 1 to 5 selected from the group consisting of C 1-5 alkoxy and a fluorine atom) 3 may be substituted with a substituent) and 4-10 membered nitrogen-containing saturated same or different 1 to 3 of which may be substituted with a substituent C 1 is selected from the group consisting of heterocyclic -10 alkyl; a C 3-8 cycloalkyl optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-5 alkoxy;
The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.
R 1 , R 2 , R 3 and R 4 are each independently the same or selected from the group consisting of a hydrogen atom; a hydroxyl group, a fluorine atom, C 1-3 alkoxy, C 1-5 alkylcarbonyl- and carbamoyl; C 1-10 alkyl optionally substituted with 1 to 3 different substituents; C optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group and a fluorine atom 3-8 cycloalkyl; or a 4- to 10-membered saturated heterocyclic ring optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-10 alkyl Yes,
Each group of R 1 -R 2 or R 3 -R 4 is a 4- to 7-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atom of each group (the substituent of the ring is The same as the substituents which may be substituted in each group constituting the ring),
The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.
Het is a divalent group of pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, triazole, thiazole, oxazole, isoxazole or isothiazole.
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.
Y is a hydrogen atom; or C 1-10 alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom, and X 1 -Y is each A 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted and contain exactly one nitrogen atom (the substituent of the ring is substituted in each group constituting the ring) The same as the substituents that may be present, and the ring may not include a morpholine ring),
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.
W is —W 1 —, —NR 7 —W 1 — or —O—W 1 —, and any one of R 3 —R 7 , R 3 —W 1 or R 7 —W 1 is A 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding a carbon atom of the group (the substituent of the ring is an optionally substituted substituent in each group constituting the ring) May be the same),
The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.
X is, -X 1 -, - X 1 -NR 5 CO-X 2 -, - X 1 -CONR 5 -X 2 - or -X 1 -O-X 2 - is and, X 1 -Y, R 1 Any one of -X 1 , R 1 -X 2 , R 1 -R 5 or R 5 -X 2 may be a 4- to 10-membered group that may be substituted by bonding of the carbon atom of each group A nitrogen-containing saturated heterocyclic ring (the substituent of the ring is the same as the substituent which may be substituted in each group constituting the ring),
The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.
X 1 is C 1-4 alkylene, and X 2 is C 2-4 alkylene.
Item 11. The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof.
Z 3 and Z 4 are each independently a hydrogen atom; C 1-10 alkyl optionally substituted with fluorine; halogen; or C 1-5 alkoxy optionally substituted with fluorine.
The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.
Het is a divalent group of pyridine or thiazole,
The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.
A therapeutic and / or prophylactic agent for a disease associated with a toll-like receptor comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient.
The therapeutic and / or prophylactic agent according to claim 15, wherein the disease associated with a toll-like receptor is sepsis, autoimmune disease or neurodegenerative disease.