JP2013147428A - Novel 2-heteroaryl monocyclic pyrimidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide prophylactic/therapeutic agents for diseases relating to autoimmunity, immunodeficiency diseases or neurodegenerative diseases, in particular prophylactic/therapeutic agents for sepsis.SOLUTION: A compound represented by formula (I) or a salt thereof is provided. In the formula: Ais formula (A) or the like; Ais formula (B) or the like; X is a 1-8C alkylene or the like; Y is a hydrogen atom, a 1-10C alkyl or the like; Het is a 5- or 6- membered heteroarylene; W is a 1-8C alkylene or the like; and Z are each independently a hydrogen atom, 1-10C alkyl or the like.

Description

  The present invention relates to a heteroaryl monocyclic pyrimidine derivative useful as a medicament. 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 types of human TLRs have been identified and named TLR1 to TLR10. Each TLR identifies the unique molecular structure (pasogen-associated molecular pattern, PAMPs) typified by cell wall components and DNA of pathogenic microorganisms, induces host immune responses, and is responsible for biological defense ( Nature Reviews Immunology, 2001, 1, 135-145). For example, TLR2 transmits signals such as peptidoglycan, which is a component of the microbial cell wall, and zymosan of yeast. TLR4 transmits lipopolysaccharide (LPS), which is a component of the Gram-negative bacterial cell wall, from the outside of the host cell into the cell. (Nature Immunology, 2001, 2, 675-680). In addition, TLR9 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 have the following diseases involving autoimmunity (sepiosis, 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 by the continuous production of antibodies or lymphocytes that react with components that constitute the tissue of the self, and is listed below (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 hematological disorders (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, nodular polyarteritis, allergic granulation Seed vasculitis, scleroderma and mixed connective tissue disease.

  On the other hand, sepsis is defined as Systemic Inflammatory Response Syndrome (SIRS) with infection (Chest, 1992, 101, 1644-1655). The cause of this is the overproduction of inflammatory mediators induced by pathogenic microorganisms and their toxins, which inflammatory mediators are also responsible for the development of septic shock and associated organ failure, as well as the induction of anti-inflammatory mediators. Has been thought to be involved.

  In recent years, drugs that suppress inflammatory mediators such as nitric oxide (NO) and cytokines have been developed based on this background, 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, an 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 sepsis-related diseases. In particular, an inhibitor against TLR9 can be expected to selectively control the immune response elicited from pathogenic microorganisms. Further, the TLR9 inhibitor can be expected to have further effects when used alone, in combination with a TLR2 inhibitor, in combination with a TLR4 inhibitor, or in combination with a TLR2 inhibitor and TLR4, and can be expected to be a fundamental treatment as a new sepsis treatment. 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.

  The present invention controls TLR-mediated innate immunity and involves autoimmunity-related diseases (sepsis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease, infection, cancer), immunodeficiency or neurodegeneration The present invention relates to a heteroaryl monocyclic pyrimidine derivative useful as a prophylactic and / or therapeutic agent for diseases (Alzheimer, Parkinson's disease, etc.).

  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) on autoimmune diseases is due to TLR9 antagonism (European Journal of Immunology, 2004, 34, 2541-2550). .

  The following representative compound (c) is also disclosed as a compound having TLR7, TLR8, and TLR9 antagonistic activity, but the structure is different from the compound of the present invention (Patent Document 1).

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.

  [Claim 1] The following formula (1):

[Wherein A ¹ represents 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, 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 is —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 ^{is, -W 1 -, - NR 7} -W 1 -, - NR 7 CO-W 1 -, - CONR 7 -W 1 - or -O-W ¹ - represents,
Here, when the nitrogen atom and W on Het rings are bonded, W is, -W ¹ - or -CONR ⁷ -W ¹ - represents,
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; an optionally substituted aryl; a cyano; _{Represents an} optionally substituted C _1-5 alkoxycarbonyl; an optionally substituted heteroaryl; a halogen; an 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 Together may form a 5-8 membered saturated or unsaturated heterocycle or saturated or unsaturated carbocycle which may be substituted,
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 heterocyclic ring,
R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ each independently represent 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 —, the carbon atom of each group of the group of R ¹ —X ¹ may be bonded and substituted. when forming a nitrogen-containing saturated heterocycle 10-membered, X ¹ is or optionally C _4-8 alkylene, optionally substituted, X ¹ is n- propylene (where position 1 of forming the ring also Third place is of a carbon atom)]
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,
(9) C _3-8 cycloalkoxy which may be substituted,
(10) C _1-5 alkoxycarbonyl,
(11) -NR ¹⁰ R ¹¹ ,
(12) -CONR ¹⁰ R ¹¹ ,
(13) optionally substituted 4 to 10-membered saturated heterocyclic ring, and (14) the same or different 1 to 5 substituents selected from the group consisting of optionally substituted C _1-5 alkylcarbonyl Optionally substituted with a group
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 the same or different 1 to 5 substituents (in this case, 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 that may be substituted with 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) C _1-5 alkoxycarbonyl, and (j) means a group optionally substituted by 1 to 5 substituents selected from the group consisting of C _1-5 alkylcarbonyl);
The optionally substituted cycloalkyl (saturated carbocyclic ring) and optionally substituted saturated heterocyclic ring are the above (a), (b), (c), (d), (h), (i) And a group which may be substituted with 1 to 5 substituents which are the same or different selected from the group consisting of (j);
In the optionally substituted aryl (unsaturated carbocycle) and optionally substituted heteroaryl (unsaturated heterocycle), the aryl part of each group is composed of the above (a) to (j) A group optionally substituted with 1 to 5 substituents which are the same or different selected from the group;
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.

[Term 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 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-10 alkyl, wherein X 1 Is —X ¹ —, X ¹ is substituted with 1 to 3 identical or different substituents selected from the group consisting of unsubstituted C _2-3 alkylene or hydroxyl group, 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. _2-8 alkylene,
X ² is C _2-8 alkylene which 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;
Y is a hydrogen atom; a C _1-10 alkyl optionally substituted with 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 - a and,
Here, when the nitrogen atom on the ring of Het and W are bonded, W is —W ¹ — or —CONR ⁷ —W ¹ —,
W ¹ is C _1-8 alkylene which 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, 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) Optionally substituted with 3 substituents) and C ₁ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of 4- to 10-membered nitrogen-containing saturated heterocycles _-10 alkyl; 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; cyano; C _1-5 alkoxycarbonyl optionally substituted with 1 fluorine atom; selected from the group consisting of halogen and C _1-10 alkyl (which group may be substituted with 1 to 3 fluorine atoms) Same or different 1 to Heteroaryl optionally substituted with 3 substituents; identical selected from the group consisting of halogen and C _1-10 alkyl, which group may be substituted with 1 to 3 fluorine atoms Or aryl optionally substituted with 1 to 3 different substituents; halogen; C ₁ optionally substituted with 1 to 3 same or different substituents selected from the group consisting of a hydroxyl group and a fluorine atom _-5 alkoxy; or a -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 identical or different substituents selected from the group consisting of a hydroxyl group and a fluorine atom; halogen Or C _1-5 alkoxy 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, or Z ³ and Z ⁴ are substituted together A 5- to 8-membered saturated or unsaturated heterocyclic ring or saturated or unsaturated carbocyclic ring which may be substituted (the substituent of the ring is the same as the optionally substituted substituent in each group constituting the ring) May be formed),
R ¹ , R ² , R ³ and R ⁴ are each independently the same or different 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. optionally substituted with 1-3 substituents C _1-10 alkyl; hydroxyl and the same or different one to three optionally substituted with a substituent C ₃ is selected from the group consisting of fluorine atoms _-8 cycloalkyl; or substituted with 1 to 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 that may be
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. 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 —, the carbon atom of each group of the group of R ¹ —X ¹ may be bonded and substituted. When forming a 10-membered nitrogen-containing saturated heterocyclic ring, X ¹ is 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 which may be substituted, or X ¹ is n-propylene (provided that the position forming the ring is the 1st or 3rd carbon atom),
Item 3. The compound according to Item 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 same group 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 heterocycles. C _1-10 alkyl; 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 1 to 3 identical or different substituents; substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group and a fluorine atom; C _3-8 cycloalkyl; or 4-10 membered saturated optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of hydroxyl, fluorine and C _1-10 alkyl A heterocycle,
Each group of R ¹ -R ² or R ³ -R ⁴ is a 4- to 7-membered nitrogen-containing saturated heterocyclic ring that may be substituted by bonding of the carbon atom of each group (the substituent on the ring is The same as the substituents 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 identical or different 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) Which may be the same as the substituents which may be substituted in
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. A 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 (the substituent of the ring is the same as the optionally substituted substituent 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.

[Item 12] 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 12. The compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.

[Item 13] Het is a divalent group of pyridine or thiazole.
Item 13. The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.

[Item 14] 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 Example 2),
5,6-dimethyl-2- (2- (piperazin-1-yl) thiazol-4-yl) -N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine (Example 3),
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 Example 7),
5,6-Dimethyl-2- (2- (4-methylpiperazin-1-yl) thiazol-4-yl) -N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine Example 8) and
5,6-Dimethyl-2- (2- (1-methylpiperidin-4-yl) thiazol-4-yl) -N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine Example 9).

  [Item 15] A pharmaceutical composition comprising the compound according to any one of Items 1 to 14 or a pharmaceutically acceptable salt thereof.

  [Item 16] 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 14 or a pharmaceutically acceptable salt thereof as an active ingredient.

  [Item 17] 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 14 or a pharmaceutically acceptable salt thereof as an active ingredient, and / or Or prophylactic agent.

  [Item 18] The therapeutic and / or prophylactic agent according to item 16, wherein the disease associated with a toll-like receptor is sepsis, autoimmune disease or neurodegenerative disease.

  [Item 19] The therapeutic and / or prophylactic agent according to item 17, wherein the disease associated with toll-like receptor 7 and / or 9 is sepsis, autoimmune disease or neurodegenerative disease.

  The compound of the present invention prevents and / or treats 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.) Moreover, 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.

The present invention is described in further detail below.
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 encompassed by the compounds of the present invention.

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

  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. -3 or 1-10 alkyl is meant, respectively. 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” means a cyclic saturated hydrocarbon group, for example, “C _3-8 cycloalkyl” means a 3- to 8-membered cyclic saturated hydrocarbon group. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferably, a 5-7 membered cycloalkyl group is mentioned.

(Iii) “Aryl” or “benzene ring to which a 5- to 8-membered saturated or unsaturated carbocycle is linked” includes a 6- to 12-membered monocyclic or bicyclic aryl group. Specific examples include phenyl, naphthyl, indenyl and the like. Preferably, a C6 monocyclic or 8-10 membered bicyclic aryl group is mentioned, for example, a phenyl and a naphthyl are mentioned.
(Iv) “Heteroaryl” or “heteroaryl ring to which a 5- to 8-membered saturated or unsaturated heterocycle is linked” is 1 to 4 selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom Examples thereof include a 5- to 7-membered monocyclic aromatic heterocycle, a 9 to 11-membered bicyclic aromatic heterocycle, and a 12 to 15-membered tricyclic aromatic heterocycle containing atoms. 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. Preferably, a 5-membered or 6-membered monocyclic aromatic heterocycle is mentioned, and specifically, pyridyl, imidazolyl, pyrazolyl, thiazolyl, indolyl or tetrazolyl can be mentioned.

(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, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, tert-pentoxy and the like. Among these, “C _1-3 alkoxy” is preferable.

(Vii) “4- to 10-membered saturated heterocyclic ring” means a saturated ring composed of 4 to 10 atoms including 1 to 3 hetero atoms in addition to carbon atoms. Specific examples include azetidinyl, pyrrolidyl, piperidyl, morpholinyl, homopiperidyl, piperazinyl, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxotetrahydrothiopyranyl, dioxotetrahydrothiopyranyl and the like. It is done. Preferably, it is a 4-7 membered saturated heterocyclic ring, and specific examples include azetidinyl, pyrrolidyl, piperidyl, morpholinyl, homopiperidyl, piperazinyl, tetrahydrofuranyl and tetrahydropyranyl. The “4 to 10-membered nitrogen-containing saturated heterocyclic ring” is 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). Preferably, it is a 4-7 membered nitrogen-containing saturated heterocyclic ring.
(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 _2-8 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 alkyl, two same or different alkyl couple | bonded with the same carbon atom may construct | assemble a ring.
(Iv) Specific examples of “C _1-5 alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl and the like. Preferably, “C _1-3 alkylcarbonyl” is exemplified, and methylcarbonyl is more preferred.

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,
(9) C _3-8 cycloalkoxy which may be substituted,
(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 the above (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 that may be substituted with 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) C _1-5 alkoxycarbonyl, and (j) means a group optionally substituted by 1 to 5 substituents selected from the group consisting of 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 for the optionally substituted cycloalkyl (saturated carbocyclic ring) and the optionally substituted saturated heterocyclic ring include the above (a), (b), (c), (d), (h) , (I) and (j). Among them, preferred is a substituent of (a), (b), (c) or (h), and more preferred is (a), a fluorine atom or (c).

  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 them, preferred is a substituent of (a), (b), (c) or (h), and more preferred is (a), a fluorine atom or (c).

  Examples of the pharmacologically 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 salt, phenylalanine addition salt, lysine addition salt, aspartic acid addition salt, glutamic acid addition salt, and the like.

Among the compounds of the present invention represented by the 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.

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 - is.
X ¹ is preferably C _1-8 alkylene which 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, and more preferably , C _1-4 alkylene.
X ² is preferably C _2-8 alkylene which 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, more preferably , C _2-6 alkylene, more preferably C _2-4 alkylene.

Y is a hydrogen atom; a C _1-10 alkyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-3 alkoxy; or a hydroxyl group; C _3-8 cycloalkyl optionally substituted with 1 to 3 identical or different 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 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 or C _1-4 alkyl.

  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. A divalent group, more preferably a divalent group of pyridine or thiazole.

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 - is.
W 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. 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 heterocyclic ring 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; cyano; 1 to 3 fluorines C _1-5 alkoxycarbonyl optionally substituted with atoms; identical selected from the group consisting of halogen and C _1-10 alkyl (which groups may be substituted with 1 to 3 fluorine atoms) Or 1-3 different The same or different selected from the group consisting of halogen and C _1-10 alkyl (which may be substituted with 1 to 3 fluorine atoms) Aryl optionally substituted by 1 to 3 substituents; halogen; C _1-5 optionally substituted by 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group and a fluorine atom Alkoxy; or —NR ⁸ R ⁹ . More preferably, a hydrogen atom; a hydroxyl group, a fluorine atom, a C _1-5 alkoxy (the group is substituted with 1 to 3 identical or different substituents selected from the group consisting of C _1-5 alkoxy and a fluorine atom. And C _1-10 alkyl optionally substituted with 1 to 3 identical or different 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 1 to 3 identical or different substituents selected from the group consisting of C _1-5 alkoxy, more preferably a hydrogen atom; a hydroxyl group, C ₁ C _1-5 alkyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of _-5 alkoxy and a 4-6 membered nitrogen-containing saturated heterocycle; or C _3-8 cyclo Alkyl.

Z ³ and Z ⁴ are preferably 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; 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 with 1 to 3 identical or different 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 saturated optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of C _1-10 alkyl, C _1-5 alkoxycarbonyl and C _1-5 alkylcarbonyl Heterocycles are mentioned. More preferably, a hydrogen atom; a C _1-10 alkyl which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group, a fluorine atom, C _1-3 alkoxy and carbamoyl; And C _3-8 cycloalkyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of fluorine atoms; or selected from the group consisting of hydroxyl groups, fluorine atoms and C _1-10 alkyls And 4- to 10-membered saturated heterocyclic rings which may be substituted with the same or different 1 to 3 substituents. More preferably, a hydrogen atom; or C _1-10 alkyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-3 alkoxy is exemplified. . Most preferably, they are a hydrogen atom or _C1-10 alkyl.

R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are preferably substituted with 1 to 3 identical or different substituents selected from the group consisting of hydrogen atom, fluorine, hydroxyl group and C _1-5 alkoxy. C _1-10 alkyl which may be _substituted is mentioned, More preferably, a hydrogen atom or C _1-10 alkyl is mentioned, More preferably, C _1-4 alkyl is mentioned.
R ¹⁰ and R ¹¹ are preferably a hydrogen atom; C _1-10 alkyl optionally substituted with 1 to 5 fluorine atoms; or 4 to 10 members 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 group which comprises). “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. In addition, the number of the nitrogen-containing saturated heterocyclic ring formed is 0-2 each independently 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 ^{preferably, r 1 -a, r 1 -b} , r 1 -c, include r ¹ -d and r ¹ -f, more ^{preferably, 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, yh, yi, and yj are mentioned, More preferably, y- a, yc, ye, yf and yh.

R ¹ -R ⁵ is, when the carbon atoms of each of the groups form a nitrogen-containing saturated heterocyclic ring bonded 4-10 optionally substituted by members, the following structures may be mentioned as preferred examples.

More ^{preferably, r 5 -a, r 5 -b} , r 5 -c, r 5 -d, and r ⁵ -e the like, 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 ^{preferably, 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 the like, more preferably X ² -a, x ² -c, x ² -d, x ² -e, x ² -f, and x ² -j.

Preferred examples when each pair 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 R ¹ —X ¹ are bonded to form an optionally substituted 4- to 10-membered nitrogen-containing saturated heterocyclic ring. when, X ¹ is or optionally C _4-8 alkylene, optionally substituted, X ¹ is a n- propylene (provided that the position of forming the ring is a carbon atom of 1-position or 3-position).

More ^{preferably, x 1 -a, x 1 -b} , x 1 -c, x 1 -d, x 1 -e, x 1 -f, include x ¹ -g and x ¹ -k, 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 the respective groups, 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 can be mentioned, 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 the respective groups, 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 the like, more ^{preferably, w 1 -a, w 1 -c} , w 1 -e, w 1 -f, it includes 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 the respective groups, 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.

Z ³ and Z ⁴ are, when forming a saturated or carbocyclic heterocyclic ring or a saturated or unsaturated unsaturated together are members 5-8 may be substituted, Z ³ and Z ⁴ are attached The following groups represented together with the heteroaryl ring are preferred examples.

[Wherein, R ^′ and R ^″ are each independently (c), (i), (j) of item 2 or a hydrogen atom, o is an integer of 1 to 4, and p is 0 to 5] , Q is an integer of 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: dimethylacetamide, 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: trifluoromethanesulfonyl Oxy, s: singlet, d: doublet, t: triplet, q: quartet, m: multit, Boc: t-butoxycarbonyl, DPPF: 1,1′-bis (diphenylphosphino) ferrocene, DPPE: 1,2- Bis (diphenylphosphino) 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 hex Fluorophosphate.

  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:
Of 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, among which 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 the presence of 1 to 5 equivalents, preferably 1.5 to 2 equivalents of a base in a solvent, 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, and among these, 1,4-dioxane, NMP or 2-propanol is preferred.
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 added 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 0.01-1 equivalents, preferably 0.05-0.2 equivalents in the presence of a phosphine ligand, 1-5 equivalents, preferably 1.1- 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. Or they can be mixed and used, 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 the phosphine ligand include monodentate ligands such as o-tolylphosphine, S-Phos or X-Phos, DPPF, DPPE, DPPP, DPPB, BINAP, XANT-Phos, DPE-Phos, etc. 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 50 to 180 ° C. or microwave irradiation, usually for 0.5 to 24 hours.

Production method 2:
Among compounds (I), compound (Ic) wherein 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, and 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]
1-10 equivalents, preferably 3-5 equivalents of a base, and 0.01-1 equivalents, preferably 0.05-0.2 equivalents of a phosphine ligand, in a solvent. And 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of palladium catalyst in the presence of 1 to 5 equivalents, preferably 1 to 2 equivalents of compound (X). Ic) can be obtained.

The solvent used in this reaction may be any as long as it is inert to the reaction, and is not particularly limited. 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, sodium acetate, and various alkali or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide can be used. Of these, cesium carbonate or sodium t-butoxide is preferred. The reaction is usually carried out for 0.5 to 24 hours under heating or microwave irradiation at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 180 ° C. 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 are as defined above. R ^b is 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 base, 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 may be any as long as it is inert to the reaction, and is not particularly limited. 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 in admixture thereof, among which 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 them, 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 and 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.

(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 Hal ^a is a chlorine atom or a bromine atom.)

[Step 9]
1-10 equivalents, preferably 1-3 equivalents of compound (XIII) and compound (II) are reacted in a solvent in the presence of 2-10 equivalents, preferably 2-4 equivalents of a base. XIV) can be obtained. Compound (XIII) is synthesized as a commercially available product or by a known method [eg, 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 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, among which 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 compounds (I), compound (Ic) in which A ¹ is formula (A), A ² is formula (B), and W is —NR ⁷ —W ¹ — is, for example, from 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 [eg, 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 which may be substituted, 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 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 lomethanesulfonate can be raised, and among them, p-toluenesulfonic 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 80 ° C., usually for 0.5 to 24 hours.

[Step 18]
1 to 10 equivalents, preferably 2 to 3 equivalents of an acid in the presence of 1 to 10 equivalents, preferably 2 to 4 equivalents of a borohydride compound, and 1 Compound (XXIII) can be obtained by reacting with 10 to 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 singly 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, among which 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:
Among compounds (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.)), 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 acid in a solvent.

The solvent used in this reaction may be any as long as it is inert to the reaction, and is not particularly limited. For example, THF, 1,4-dioxane, diethyl ether, dichloromethane, DCE, methanol, ethanol and the like alone or They can be used as a mixture, and among these, 1,4-dioxane, dichloromethane 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 them, 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 compound (I), may be Z ¹ is substituted C _1-5 alkoxy group, with -NR ⁹ R ^10, C _1-5 alkyl substituted with a nitrogen-containing saturated heterocyclic ring such as a 4-10 membered 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 , 4- to 10-membered nitrogen-containing saturated heterocyclic ring, etc.)

[Step 25]
For example, compound (XXX) can be obtained by reacting compound (XXIX) obtained by a method according to WO2005110416 and compound (V) in the same manner as in Step 3.

[Step 26]
Compound (XXX) obtained in Step 25 is optionally added in the presence of 1 to 10 equivalents, preferably 2 to 5 equivalents of a base in a solvent in the presence of 1 to 20 equivalents, preferably 3 to 10 equivalents of compound (XXXI). ) To give compound (XXXII).

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, among which 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 20-80 ° C., usually for 0.5-24 hours.

[Step 27]
Compound (Ih) can be obtained by reacting compound (XXXII) obtained in step 26 with compound (VII) in the same manner as in step 4.

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

(In the formula, 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 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 Iternational 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 an amount of 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalent of palladium catalyst in a solvent in the presence of 0.01 to 1 equivalent, preferably 1.1 to 2. 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 can be 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, among which tetrakistriphenylphosphine palladium or bis (t-butylphosphine) palladium is 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.

(In the formula, 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 a bromine atom, Hal ^d is a chlorine atom, a bromine atom or an iodine atom, and Hal ^e is a bromine atom or an iodine atom.)

[Step 31]
By reacting a commercially available product or 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, and 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 by 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 obtain 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 the phosphine ligand include monodentate ligands such as o-tolylphosphine, S-Phos or X-Phos, DPPF, DPPE, DPPP, DPPB, BINAP, XANT-Phos, DPE-Phos, etc. 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 50 to 180 ° C. or 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 them, 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 to 40 ° C., usually for 0.5 to 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.
Depending on the reaction conditions and the like, some of the raw material compounds or intermediates in the above production method may exist in the form of a salt such as hydrochloride, but can be used as they are 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 pharmaceutically acceptable carriers. Examples of the pharmaceutical carrier to be 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 ingredients ranges from about 0.0001 to about 2000 mg, preferably from about 0.001 to about 1000 mg, more preferably from about 0.1 to about 500 mg, particularly preferably from about 1 to about 300 mg. It can be administered once or several times a day.

  EXAMPLES Hereinafter, although an Example and a reference example are given and this invention is demonstrated more concretely, 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) 2,4-Dichloro-5,6-dimethylpyrimidine
To 5,6-dimethyluracil (2.0 g, 14.3 mmol), phosphorus oxychloride (13 ml) was added and 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 (CDCl3, 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 Compound 1A (1.51 g, 8.53 mmol) obtained above in 2-propanol 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 resulting 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) To the solution were added 1- (3-aminopropyl) -2-pyrrolidinone (1.58 ml, 11.3 mmol) and N, N-diisopropylethylamine (1.97 ml, 11.3 mmol), 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 resulting 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, liquid separation and extraction were performed with chloroform-water, and the organic layer was washed with a saturated saline solution and then distilled off 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 tetrahydrofuran (25 ml) solution of compound 3A (1.45 g, 4.16 mmol) synthesized by the method described in WO2006072436 was cooled to −78 ° C., and a 1.65 M butyllithium hexane solution (3.15 ml, 5.20 mmol) was added dropwise. 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, using the compound 4A synthesized by the method described in WO2009045992, the title compound was obtained by synthesis in the same manner as in Reference Example 6 (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 8)
tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiazol-2-yl) piperazine-1-carboxylate

For example, using the compound 5A synthesized by the method described in WO2009145360, the title compound was obtained by synthesis in the same manner as in Reference Example 6 (yield 23%).
¹ H-NMR (CDCl ₃ , δ ppm): 7.65 (1H, s), 3.48-3.55 (8H, m), 1.46 (9H, s), 1.30 (12H, 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, 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 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, followed by stirring 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).

Examples 2 and 3 :
Reaction and treatment were performed in the same manner as in Example 1 using the corresponding starting compounds, and the compounds shown in Table 2 were obtained.

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 hour and a half, liquid separation extraction was performed with chloroform-water, and the organic layer was washed with a saturated saline solution 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 ul), formaldehyde (33.9 ul, 0.411 mmol), sodium cyanoborohydride (25.8 mg, 0.411 mmol) 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 8)
5,6-Dimethyl-2- (2- (4-methylpiperazin-1-yl) thiazol-4-yl) -N- (3- (pyrrolidin-1-yl) propyl) pyrimidin-4-amine

The title compound was obtained in the same manner as in Example 7 using the compound obtained in Example 3 (yield 67%).
¹ H-NMR (CDCl ₃ , δ ppm): 7.90 (1H, s), 6.86-6.91 (1H, m), 3.53-3.60 (6H, m), 2.63-2.67 (2H, m), 2.48-2.53 ( 8H, m), 2.32 (3H, s), 2.31 (3H, s), 1.90 (3H, s), 1.78-1.84 (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 and extraction were performed with an aqueous chloroform-sodium hydroxide solution, 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 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).

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 TLR9 Reporter Gene Test HEK293 cell stable human TLR9 expression strain (human TLR9-293 cell) was put to sleep and the passage was repeated until the cell state was stabilized. 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 centrifuged cell pellet was suspended in a growth medium. Human TLR9-293 cells prepared at 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 at 80 μL / well in a 96-well black plate (5 × 10 ⁴ cells / well). 10 μL each of the test substance (final concentration: 1, 3, 10, 30, 100, 300, 1000 nM) and CpG2006 (final concentration 150 nM) were added, followed by culturing 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 compounds of the present invention exhibited a strong inhibitory action in the NF-kB inhibition test. The compounds of Examples 1, 3, and 8 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 on the slide glass. After centrifugation, hemolysis was performed using ACK. Medium was added to stop the ACK reaction, and centrifugation was performed. Cells were prepared at 1 × 10 ⁷ cells / mL and seeded at 100 μL / well in a 96-well plate (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 (final concentration 100 nM) in a CO 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. Moreover, the compound which showed the high activity value by the NF-kB inhibition test shown in Table 5 showed the strong IL-6 production inhibitory effect similarly to the said Example 1. FIG.

  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 prophylactic and / or therapeutic agent for inflammation, allergy, asthma, graft rejection, graft-versus-host disease, infection, cancer), immunodeficiency or neurodegenerative diseases (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 (16)

Formula (1):

[Wherein A ¹ represents 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, 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 is —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 ^{is, -W 1 -, - NR 7} -W 1 -, - NR 7 CO-W 1 -, - CONR 7 -W 1 - or -O-W ¹ - represents,
Here, when the nitrogen atom and W on Het rings are bonded, W is, -W ¹ - or -CONR ⁷ -W ¹ - represents,
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; an optionally substituted aryl; a cyano; _{Represents an} optionally substituted C _1-5 alkoxycarbonyl; an optionally substituted heteroaryl; a halogen; an 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 Together may form a 5-8 membered saturated or unsaturated heterocycle or saturated or unsaturated carbocycle which may be substituted,
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 heterocyclic ring,
R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ each independently represent 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 —, the carbon atom of each group of the group of R ¹ —X ¹ may be bonded and substituted. when forming a nitrogen-containing saturated heterocycle 10-membered, X ¹ is or optionally C _4-8 alkylene, optionally substituted, X ¹ is n- propylene (where position 1 of forming the ring also Third place is of a carbon atom)]
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,
(9) C _3-8 cycloalkoxy which may be substituted,
(10) C _1-5 alkoxycarbonyl,
(11) -NR ¹⁰ R ¹¹ ,
(12) -CONR ¹⁰ R ¹¹ ,
(13) optionally substituted 4 to 10-membered saturated heterocyclic ring, and (14) the same or different 1 to 5 substituents selected from the group consisting of optionally substituted C _1-5 alkylcarbonyl Optionally substituted with a group
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 the same or different 1 to 5 substituents (in this case, 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 that may be substituted with 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) C _1-5 alkoxycarbonyl, and (j) means a group optionally substituted by 1 to 5 substituents selected from the group consisting of C _1-5 alkylcarbonyl);
The optionally substituted cycloalkyl (saturated carbocyclic ring) and optionally substituted saturated heterocyclic ring are the above (a), (b), (c), (d), (h), (i) And a group which may be substituted with 1 to 5 substituents which are the same or different selected from the group consisting of (j);
In the optionally substituted aryl (unsaturated carbocycle) and optionally substituted heteroaryl (unsaturated heterocycle), the aryl part of each group is composed of the above (a) to (j) A group optionally substituted with 1 to 5 substituents which are the same or different selected from the group;
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 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-10 alkyl, wherein X 1 Is —X ¹ —, X ¹ is substituted with 1 to 3 identical or different substituents selected from the group consisting of unsubstituted C _2-3 alkylene or hydroxyl group, 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. _2-8 alkylene,
X ² is C _2-8 alkylene which 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;
Y is a hydrogen atom; a C _1-10 alkyl optionally substituted with 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 - a and,
Here, when the nitrogen atom on the ring of Het and W are bonded, W is —W ¹ — or —CONR ⁷ —W ¹ —,
W ¹ is C _1-8 alkylene which 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, 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) Optionally substituted with 3 substituents) and C ₁ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of 4- to 10-membered nitrogen-containing saturated heterocycles _-10 alkyl; 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; cyano; C _1-5 alkoxycarbonyl optionally substituted with 1 fluorine atom; selected from the group consisting of halogen and C _1-10 alkyl (which group may be substituted with 1 to 3 fluorine atoms) Same or different 1 to Heteroaryl optionally substituted with 3 substituents; identical selected from the group consisting of halogen and C _1-10 alkyl, which group may be substituted with 1 to 3 fluorine atoms Or aryl optionally substituted with 1 to 3 different substituents; halogen; C ₁ optionally substituted with 1 to 3 same or different substituents selected from the group consisting of a hydroxyl group and a fluorine atom _-5 alkoxy; or a -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 identical or different substituents selected from the group consisting of a hydroxyl group and a fluorine atom; halogen Or C _1-5 alkoxy 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, or Z ³ and Z ⁴ are substituted together A 5- to 8-membered saturated or unsaturated heterocyclic ring or saturated or unsaturated carbocyclic ring which may be substituted (the substituent of the ring is the same as the optionally substituted substituent in each group constituting the ring) May be formed),
R ¹ , R ² , R ³ and R ⁴ are each independently the same or different 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. optionally substituted with 1-3 substituents C _1-10 alkyl; hydroxyl and the same or different one to three optionally substituted with a substituent C ₃ is selected from the group consisting of fluorine atoms _-8 cycloalkyl; or substituted with 1 to 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 that may be
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. 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 —, the carbon atom of each group of the group of R ¹ —X ¹ may be bonded and substituted. When forming a 10-membered nitrogen-containing saturated heterocyclic ring, X ¹ is 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 which may be substituted, or X ¹ is n-propylene (provided that the position forming the ring is the 1st or 3rd carbon atom),
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 as described in any one of Claims 1-3, or its pharmaceutically acceptable salt. 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) Optionally substituted with 3 substituents) and C ₁ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of 4- to 10-membered nitrogen-containing saturated heterocycles _-10 alkyl; a C _3-8 cycloalkyl optionally substituted by 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C _1-5 alkoxy;
The compound as described in any one of Claims 1-4, or its pharmaceutically acceptable salt. R ¹ , R ² , R ³ and R ⁴ are each independently the same or different 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. optionally substituted with 1-3 substituents C _1-10 alkyl; hydroxyl and the same or different one to three optionally substituted with a substituent C ₃ is selected from the group consisting of fluorine atoms _-8 cycloalkyl; or a 4 to 10 membered saturated heterocyclic ring optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of hydroxyl, fluorine and C _1-10 alkyl ,
Each group of R ¹ -R ² or R ³ -R ⁴ is a 4- to 7-membered nitrogen-containing saturated heterocyclic ring that may be substituted by bonding of the carbon atom of each group (the substituent on the ring is The same as the substituents which may be substituted in each group constituting the ring),
The compound as described in any one of Claims 1-5, or its pharmaceutically acceptable salt. Het is a divalent group of pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, triazole, thiazole, oxazole, isoxazole or isothiazole.
The compound as described in any one of Claims 1-6, or its pharmaceutically acceptable salt. Y is a hydrogen atom; or C _1-10 alkyl optionally substituted with 1 to 3 identical or different 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) Which may be the same as the substituent (s) that may be
The compound as described in any one of Claims 1-7, or its pharmaceutically acceptable salt. 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 as described in any one of Claims 1-8, or its pharmaceutically acceptable salt. 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 atoms of the respective groups; 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 as described in any one of Claims 1-9, or its pharmaceutically acceptable salt. X ¹ is C _1-4 alkylene, 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.